Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them

ABSTRACT

The invention relates to new substituted 1-phenyl-3-pyrazolecarboxamides having a great affinity for human neurotensin receptors, to a process for preparing them and to pharmaceutical compositions containing them as active principles. More particularly, this invention relates to the discovery that the affinity for neurotensin receptors, especially human neurotensin receptors, is increased by substituting the phenyl group of 1-phenyl-3-pyrazolecarboxamide compounds with particular groups.

The present invention relates to new substituted1-phenyl-3-pyrazolecarboxamides having a great affinity for humanneurotensin receptors, to a process for preparing them and topharmaceutical compositions containing them as active principles.

The first synthetic non-peptide potential medicinal products capable ofbinding to neutotensin receptors have been described in EP-0,477,049.They are amides of 3-pyrazolecarboxylic acid, variously substituted withamino acids, which displace iodinated neurotensin from its receptor, atdoses of less than one micromole, on guinea pig brain membranes. Thisseries led to the development of a compound, 2-(1-(7-chloro-4-quinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl)carbonylamino!-2-adamantanecarboxylicacid, SR 48692, endowed with potent and selective neurotensin-antagonistactivity (D. Gully et al., Proc. Natl. Acad. Sci. USA, 1993, 90, 65-69).

The feature of the series of products described in EP-0,477,049 is thepresence at position 1 of the pyrazole ring of, in particular, a phenyl,naphthyl or 4-quinolyl group, substituted or unsubstituted. Moreespecially, SR 48692 possesses a 7-chloro-4-quinolyl group in position 1of the pyrazole. The products described in this document having a1-naphthyl or 4-chloro-1-naphthyl group in position 1 of the pyrazolering have an extremely high affinity for the guinea pig neurotensinreceptor, since their IC₅₀ is of the order of 1 to 10 nanomoles, whereastheir affinity for the human receptor is lower since their IC₅₀ is from10 to 100 nmol.

It has now been found that, by substituting the phenyl group of1-phenyl-3-pyrazolecarboxamide compounds with particular groups, theaffinity for neurotensin receptors is increased, and more especially theaffinity for human neurotensin receptors is increased.

In addition, the compounds according to the present invention show invivo a broader spectrum of activity than the compounds described inEP-0,477,049 as antagonists of the neurotensin receptors.

Thus, the present invention relates, according to one of its aspects, tonew substituted 1-phenyl-3-pyrazolecarboxamides of formula: ##STR1## inwhich: --R₁ represents a group chosen from:

--T--CN;

--C(NH₂)═NOH;

--C(═NOH)NH(CH₂)_(r) NR₅ R₆ ;

--T--C(NR₁₂ R₁₃)═NR₁₄ ;

--C(NH₂)═NO(CH₂)_(r) NR₅ R₆ ;

--T--CONR_(a) R_(b) ;

--T--CONR₇ R_(c) ;

--Y--CO₂ R₇ ;

--OR_(d) ;

--T--NR₅ R₆, on condition that R₅ and R₆ do not simultaneously representhydrogen when T represents a direct bond;

--T--N(R₇)COR_(e) ;

--SO₂ NR_(a) R_(b) ;

--T--N(R₇)SO₂ R'₇ ;

--T--NR₂₇ R₂₈ ;

--NR_(a) R_(b) represents a group chosen from: ##STR2## --NR₇ (CH₂)_(q)CN; --NR₇ (CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄ ;

--NR₇ (CH₂)_(q) CONH₂ ; --NR₇ (CH₂)_(q) CO₂ R₇);

--NR₂₁ (CH₂)_(s) CR₇ R₈ (CH₂)_(t) NR₂₅ R₂₆ ;

R_(c) represents a group chosen from:

--X--OR₇ ; --CHR₂₀ CO₂ R₇ ; --(CH₂)₄ CH(NH₂)CO₂ R₇ ;

R_(d) represents a group chosen from:

--X--NR₅ R₆ ; --Y--CONR₅ R₆ ; --Y--CO₂ R₇ ; --Y--SO₂ NR₅ R₆ ; ##STR3##R_(e) represents a group chosen from: ##STR4## --(CH₂)_(q) C(NR₁₂R₁₃)═NR₁₄ ; --NR₁₈ R₁₉ ;

R₂ and R₃ each independently represent hydrogen, a (C₁ -C₆)alkyl, a (C₃-C₈)cycloalkylmethyl, a (C₃ -C₈)cycloalkyl, a halogen, a nitro, atrifluoromethyl, a group --OR₄, a group --NR₅ R₆, a 1-pyrrolyl, a cyano,a carbamoyl;

or R₂ and R₃ together constitute a trimethylene, tetramethylene orpentamethylene group;

R₄ represents hydrogen; a (C₁ -C₆)alkyl; a (C₃ -C₄)alkenyl; a (C₃-C₈)cycloalkyl; a (C₃ -C₈)cycloalkylmethyl; a (C₁ -C₄)alkoxy(C₁-C₄)alkylene; a benzyl;

R₅ and R₆ each independently represent a hydrogen, a (C₁ -C₆)alkyl; a(C₃ -C₈)alkenyl; a (C₃ -C₈)cycloalkylmethyl; a benzyl; or R₅ and R₆,together with the nitrogen atom to which they are attached, represent aheterocycle chosen from: pyrrolidine, piperidine, morpholine,thiomorpholine, piperazine substituted at position 4 with R₉, aziridine,azetidine and perhydroazepine;

R'₅ and R'₆ each independently represent a hydrogen or a (C₁ -C₆)alkyl;or alternatively, R'₅ and R'₆, together with the nitrogen atom to whichthey are attached, represent a heterocycle chosen from: pyrrolidine,piperidine, morpholine, thiomorpholine and piperazine which isunsubstituted or substituted at position 4 with a (C₁ -C₆)alkyl;

R'₇ represents a (C₁ -C₄)alkyl; a phenyl which is unsubstituted orsubstituted one or more times with a (C₁ -C₄)alkyl; a group --X--NR₅ R₆;

R₇ represents a hydrogen, a (C₁ -C₄)alkyl or a benzyl;

R₈ represents a hydrogen, a (C₁ -C₄)alkyl, a hydroxyl, or R₇ and R₈,together with the carbon atom to which they are attached, constitute a(C₃ -C₅)cycloalkane;

R₉ represents hydrogen, a (C₁ -C₄)alkyl, a benzyl, a group --X--OH or agroup --X--NR'₅ R'₆, a (C₃ -C₈)alkenyl;

R₁₀ represents a hydrogen, a (C₁ -C₄)alkyl, a benzyl, a carbamoyl, acyano;

R₁₁ represents a hydrogen, a (C₁ -C₄)alkyl, a group --X--OH, a group--X--NR'₅ R'₆ ;

R₁₂ and R₁₃ each independently represent a hydrogen or a (C₁ -C₄)alkyl;

R₁₄ represents hydrogen, R₁₄ can, in addition, represent a (C₁ -C₄)alkylwhen R₁₂ represents hydrogen and R₁₃ represents a (C₁ -C₄)alkyl;

or R₁₃ and R₁₄ together represent a group Z;

R₁₅ represents hydrogen, a (C₁ -C₄)alkyl, a group --(CH₂)_(S) NR₅ R₆ ;

R₁₆ represents hydrogen, a (C₁ -C₈)alkyl, a (C₃ -C₈)-cycloalkyl, aphenyl, a 2-piperidyl, a 3-piperidyl, a 4-piperidyl;

R₁₇ represents a (C₁ -C₆)alkyl, a phenyl, a benzyl, a hydroxy(C₁-C₄)alkyl, an amino(C₁ -C₄)alkyl;

R₁₈ and R₁₉ each independently represent a hydrogen, a (C₁ -C₄)alkyl;R₁₈ can, in addition, represent a group --(CH₂)_(q) --NR₅ R₆ ;

or R₁₈ and R₁₉, together with the nitrogen atom to which they areattached, represent a heterocycle chosen from: pyrrolidine, piperidine,morpholine, thiomorpholine, piperazine substituted at position 4 with R₉;

R₂₀ represents hydrogen, a (C₁ -C₄)alkyl, a benzyl, ahydroxyphenylmethyl, preferably a 4-hydroxyphenyl-methyl, a hydroxy(C₁-C₄)alkyl, a mercapto(C₁ -C₄) alkyl; a --(CH₂)₃ --NH--C(═NH)NH₂ group, a--(CH₂)₄ NH₂ group, a group --CH₂ --Im in which Im represents a4-imidazolyl;

R₂₁ represents a (C₁ -C₄)alkyl, an allyl or a benzyl;

R₂₂ and R₂₃ each independently represent a (C₁ -C₆)alkyl; oralternatively R₂₂ and R₂₃, together with the nitrogen atom to which theyare attached, represent a heterocycle chosen from: pyrrolidine,piperidine, morpholine and perhydroazepine;

R₂₄ represents a (C₁ -C₄)alkyl, a benzyl, an allyl, a hydroxy(C₁-C₄)alkyl, a (C₁ -C₄)alkoxy(C₁ -C₄)alkyl;

Q.sup.⊖ represents an anion;

R₂₅ represents hydrogen or a (C₁ -C₆)alkyl;

R₂₆ represents a (C₁ -C₄)alkoxycarbonyl, a benzyloxycarbonyl; a (C₁-C₄)alkylcarbonyl;

R₂₇ represents a hydrogen; a (C₁ -C₄)alkyl, a (C₁ -C₄)alkylcarbonyl; agroup --CO--(CH₂)_(r) --OH; a group SO₂ R'₇ ;

R₂₈ represents a group --X--NR₅ R₆ ;

s=0 to 3;

t=0 to 3, on the condition that (s+t), in a same group, is greater thanor equal to 1;

r=2 to 5;

q=1 to 5;

T represents a direct bond or (C₁ -C₇)alkylene;

X represents a (C₂ -C₇)alkylene;

Y represents a (C₁ -C₇)alkylene;

Z represents a (C₂ -C₆)alkylene;

the bivalent radicals A and E, together with the carbon atom and thenitrogen atom to which they are attached, constitute a saturated 4- to7-membered heterocycle which can, in addition, be substituted with oneor more (C₁ -C₄)alkyls;

the bivalent radicals G and L, together with the nitrogen atoms to whichthey are attached, constitute a piperazine or imidazolidine orimidazoline ring, the said rings being optionally substituted on thecarbon atoms with one or more (C₁ -C₄)alkyls;

the group --NH--AA(OH) represents the residue of an amino acid: ##STR5##where X_(a) is hydrogen and X'_(a) is hydrogen, a (C₁ -C₅)alkyl or anon-aromatic C₃ -C₁₅ carbocyclic radical; or alternatively, X_(a) andX'_(a), together with the carbon atom to which they are attached, form anon-aromatic C₃ -C₁₅ carbocycle;

their salts and their quaternary ammonium salts formed with acyclic orcyclic tertiary amines and their solvates.

When a compound according to the invention comprises one or moreasymmetric carbon atoms, each of the optical isomers forms part of theinvention, as does the racemic form.

When a compound according to the invention possesses several tautomericforms, each of these forms part of the invention. This is the case, inparticular, when the substituent R₁ contains a substituted amidine group--C(NR₁₂ R₁₃)═NR₁₄.

When the group --NH(AA)OH represents the residue of a cycloaliphaticamino acid, the amino or amino-methyl groups may be in the endo positionor in the exo position with respect to the ring system; in both cases,the compounds of formula (I) form part of the invention.

According to the present invention, alkyl or alkylene is understood tomean an unbranched or branched alkyl or alkylene qualified by the numberof carbon atoms it contains; halogen is understood to mean a chlorine,bromine, fluorine or iodine atom.

Non-aromatic C₃ -C₁₅ carbocyclic radicals comprise saturated orunsaturated, fused or bridged mono- or polycyclic radicals, optionallyterpenic. These radicals are optionally mono- or polysubstituted with aC₁ -C₄ alkyl.

Monocyclic radicals include cycloalkyls, for example cyclopropyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl.

In the above residue of the amino acid, when X_(a) and X'_(a), togetherwith the carbon atom to which they are attached, form a non-aromatic C₃-C₁₅ carbocycle, the said carbocycle is as defined for the correspondingradicals above.

Among polycyclic non-aromatic carbocycles, adamantane, bicyclo3.3.1!nonane and norbornane are the preferred members. The radicalcorresponding to adamantane may be 1-adamantyl when X_(a) is hydrogen,or 2-adamantylidene when X_(a) and X'_(a), together with the carbon atomto which they are attached, form a carbocycle.

Among monocyclic non-aromatic carbocycles, cyclopentane and cyclohexaneare especially preferred.

The salts of the compounds of the invention can be internal salts oralternatively salts with alkali metals, preferably sodium or potassium,and alkaline-earth metals, preferably calcium, and with organic basessuch as diethylamine, tromethamine, meglumine (N-methyl-D-glucamine),lysine, arginine, histidine, choline or diethanolamine, or opticallypure organic bases such as α-methylbenzylamine.

The salts of the compounds of formula (I) according to the presentinvention also comprise those with inorganic or organic acids whichpermit an appropriate separation or crystallization of the compounds offormula I, such as picric acid, oxalic acid or an optically active acid,for example a mandelic acid or a camphorsulphonic acid, and preferablythose which form pharmaceutically acceptable salts such as thehydrochloride, acetate, hydrogen sulphate, dihydrogen phosphate,methanesulphonate, maleate, fumarate, 2-naphthalenesulphonate,isethionate, benzenesulphonate, para-toluenesulphonate, tartrate,citrate or edisilate.

The quaternary ammonium salts with acyclic or cyclic tertiary amines areformed by substitution of the amine with a (C₁ -C₄)alkyl, a benzyl, anallyl, a hydroxy(C₁ -C₄)alkyl or a (C₁ -C₄)alkoxy(C₁ -C₄)alkylene; theanion preferably being a pharmaceutically acceptable anion.

Advantageously, the invention relates to compounds of formula (Ip):##STR6## in which: R_(1p) represents a group chosen from:

--T--CN;

--C(NH₂)═NOH;

--C(--NOH)NH(CH₂)_(r) NR₅ R₆ ;

--T--C(NR₁₂ R₁₃)═NR₁₄ ;

--C(NH₂)═NO(CH₂)_(r) NR₅ R₆ ;

--T--CONR_(a) R_(b) ;

--T--CONR₇ R_(c) ;

--Y--CO₂ R₇ ;

--OR_(d) ;

--T--NR₅ R₆, on condition that R₅ and R₆ do not simultaneously representhydrogen when T represents a direct bond;

--T--N(R₇)COR_(e) ;

--SO₂ NR_(a) R_(b) ;

--T--N(R₇)SO₂ R'₇ ;

--NR_(a) R_(b) represents a group chosen from:

--NR₅ R₆ ; --NR₉ (CH₂)_(s) CR₇ R₈ (CH₂)_(t) NR₅ R₆ ; ##STR7## --NR₇(CH₂)_(q) CN; --NR₇ (CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄ ;

R_(c) represents a group chosen from:

--X--OR₇ ; --CHR₂₀ CO₂ R₇ ; --(CH₂)₄ CH((NH₂)CO₂ R₇ ;

R_(d) represents a group chosen from: ##STR8## R_(e) represents a groupchosen from: ##STR9## --(CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄ ; --NR₁₈ R₁₉ ;

R_(2p) and R_(3p) each independently represent hydrogen, a (C₁-C₆)alkyl, a (C₃ -C₈)cycloalkylmethyl, a (C₃ -C₄)cycloalkyl, a halogen,a nitro, a trifluoromethyl, a group --OR₄, a group --NR₅ R₆, a1-pyrrolyl, a cyano, a carbamoyl;

or R_(2p) and R_(3p) together constitute a trimethylene, tetramethyleneor pentamethylene group;

R_(4p) represents hydrogen; a (C₁ -C₆)alkyl; a (C₃ -C₄)alkenyl; a (C₃-C₈)cycloalkyl; a (C₃ -C₈)cycloalkylmethyl; a (C₁ -C₄)alkoxy(C₁-C₄)alkyl; a benzyl;

R₅ and R₆ each independently represent a hydrogen, a (C₁ -C₆)alkyl; orR₅ and R₆, together with the nitrogen atom to which they are attached,represent a heterocycle chosen from: pyrrolidine, piperidine,morpholine, thiomorpholine, piperazine substituted at position 4 with R₉;

R'₇ represents a (C₁ -C₄)alkyl;

R₇ represents a hydrogen, a (C₁ -C₄)alkyl or a benzyl;

R₈ represents a hydrogen, a (C₁ -C₄)alkyl, a hydroxyl, or R₇ and R₈,together with the carbon atom to which they are attached, constitute a(C₃ -C₅)cycloalkane;

R₉ represents hydrogen, a methyl, a group --X--OH or a group --X--NR₅ R₆;

R₁₀ represents a hydrogen, a (C₁ -C₄)alkyl, a benzyl, a carbamoyl, acyano;

R₁₁ represents a hydrogen, a (C₁ -C₄)alkyl, a group --X--OH, a group--X--NR₅ R₆ ;

R₁₂ and R₁₃ each independently represent a hydrogen or a (C₁ -C₄)alkyl;

R₁₄ represents hydrogen, R₁₄ can, in addition, represent a (C₁ -C₄)alkylwhen R₁₂ represents hydrogen and R₁₃ represents a (C₁ -C₄)alkyl;

or R₁₃ and R₁₄ together represent a group Z;

R₁₅ represents hydrogen, a (C₁ -C₄)alkyl, a group --(CH₂)_(s) NR₅ R₆ ;

R₁₆ represents hydrogen, a (C₁ -C₈)alkyl, a (C₃ -C₈)cycloalkyl, aphenyl, a 2-piperidyl, a 3-piperidyl, a 4-piperidyl;

R₁₇ represents a (C₁ -C₆)alkyl, a phenyl, a benzyl, a hydroxy(C₁-C₄)alkyl, an amino(C₁ -C₄)alkyl;

R₁₈ and R₁₉ each independently represent a hydrogen, a (C₁ -C₄)alkyl;R₁₈ can, in addition, represent a group --(CH₂)_(q) --NR₅ R₆ ;

or R₁₈ and R₁₉, together with the nitrogen atom to which they areattached, represent a heterocycle chosen from: pyrrolidine, piperidine,morpholine, thiomorpholine, piperazine substituted at position 4 with R₉;

R₂₀ represents hydrogen, a (C₁ -C₄)alkyl, a benzyl, ahydroxyphenylmethyl, a hydroxy(C₁ -C₄)alkyl, a mercapto(C₁ -C₄)alkyl; a--(CH₂)₃ --NH--C(═NH)NH₂ group, a --(CH₂)₄ NH₂ group, a group --CH₂ --Imin which Im represents a 4-imidazolyl;

s=0 to 3;

t=0 to 3, on the condition that (s+t) is greater than or equal to 1;

r=2 to 5;

q=1 to 5;

T represents a direct bond or (C₁ -C₇)alkylene;

X represents a (C₂ -C₇)alkylene;

Y represents a (C₁ -C₇)alkylene;

Z represents a (C₂ -C₆)alkylene;

the bivalent radicals A and E, together with the carbon atom and thenitrogen atom to which they are attached, constitute a saturated 5- to7-membered heterocycle which can, in addition, be substituted with oneor more (C₁ -C₄)alkyls;

the bivalent radicals G and L, together with the nitrogen atoms to whichthey are attached, constitute a piperazine or imidazolidine orimidazoline ring, the said rings being optionally substituted on thecarbon atoms with one or more (C₁ -C₄)alkyls;

the group --NH--AA_(p) (OH) represents the residue of an amino acid:##STR10## where X_(a) is hydrogen and X'_(a) is hydrogen, a (C₁-C₅)alkyl or a non-aromatic C₃ -C₁₅ carbocyclic radical; oralternatively X_(a) and X'_(a), together with the carbon atom to whichthey are attached, form a non-aromatic C₃ -C₁₅ carbocycle; and theirsalts.

Preferred compounds according to the invention correspond to theformula: ##STR11## in which: R"₄ represents hydrogen, a methyl or acyclopropylmethyl;

AA"(OH) represents a 2-carboxy-2-adamantyl, α-carboxycyclohexylmethyl or9-carboxybicyclo 3.3.1!nonan-9-yl group;

among the substituents w₂, w₃, w₄ and w₅, at least one is hydrogen andat least one other is other than hydrogen, such that: either

(i)

w₅ is hydrogen;

w₃ is hydrogen or methyl;

w₂ is (C₁ -C₄)alkyl, (C₃ -C₆)cycloalkyl, (C₁ -C₄)alkoxy, chlorine ortrifluoromethyl, or w₂ and w₃ together form a 1,4-butylene group;

w₄ is chosen either from the following groups:

(i1) dialkylaminoalkylaminocarbonyl ##STR12## (i2)dialkylaminoalkyl(N-methyl)aminocarbonyl ##STR13## (i3)dialkylaminoalkyl(N-ethyl)aminocarbonyl ##STR14## (i4)cyanoalkyl(N-methyl)aminocarbonyl ##STR15## (i5) aminoalkylaminocarbonylH₂ N--ALK--NH--CO--

(i6) aminoalkyl(N-methyl)aminocarbonyl ##STR16## (i7)(N'-methyl)-(N'-alkoxycarbonyl)aminoalkyl-(N-methyl)carbonyl ##STR17##(i8)amidinoalkylaminocarbonyl ##STR18##(i9)pyrrolidinoalkylaminocarbonyl ##STR19##(i10)morpholinoalkylaminocarbonyl ##STR20##(i11)alkylaminoalkyl(N-methyl)aminocarbonyl ##STR21## (i12)2(1H)-imidazolinylalkylaminocarbonyl ##STR22## (i13)bis(dialkylaminoalkyl)aminocarbonyl (ALK₂ N--ALK')₂ N--CO--

(i14) aminocarbonylalkyl(N-methyl)aminocarbonyl ##STR23## (i15)carboxyalkyl(N-methyl)aminocarbonyl ##STR24## (i16) a group of structure##STR25## (i17) 2-pyridylaminocarbonyl ##STR26## (i18)1-benzyl-4-piperidylaminocarbonyl ##STR27## (i19)3-quinuclidinylaminocarbonyl ##STR28## (i20) 4-piperidylaminocarbonyl##STR29## (i21) 2,2,6,6-tetramethyl-4-piperidylaminocarbonyl ##STR30##(i22) aminocarbonyl H₂ N--CO--

(i23) 4-alkylpiperazinocarbonyl ##STR31## (i24)4-dialkylaminopiperidinocarbonyl ##STR32## (i25)3-dialkylaminopyrrolidinocarbonyl ##STR33## (i26)dialkylaminoalkyl(N-methyl)aminosulphonyl ##STR34## (i27)dialkylaminoalkyl(N-benzyl)aminosulphonyl ##STR35## (i28)1-alkyl-2-pyrrolidinylmethylaminocarbonyl ##STR36## (i29)allylaminocarbonyl CH₂ ═CH--CH₂ --NH--CO--

(i30) dialkylaminoalkyl(N-acetyl)amino ##STR37## (i31)dialkylaminoalkylamino ##STR38## (i32) dialkylaminoalkylcarboxamido##STR39## or alternatively w₄ is chosen from the following groups: (i33)piperidinoalkylcarboxamido ##STR40## (i34) glycinamido H₂ N--CH₂--CO--NH--

(i35) tosylamido ##STR41## (i36) aminoalkylsulphonamido H₂ N--ALK'--SO₂NH-- or H₂ N--CH₂ --SO₂ NH--

(i37) trialkylammonioalkyl(N-methyl)aminocarbonyl salt ##STR42## ALKbeing (C₁ -C₄)alkyl and ALK' being (C₂ -C₅)alkylene;

or

(ii)

w₂ and w₅ are hydrogen

w₃ is chlorine

w₄ is cyano or aminocarbonyl

or

(iii)

w₂ and w₅ are hydrogen, w₃ is isopropyl and w₄ isdialkylaminoalkylaminocarbonyl ##STR43## ALK and ALK' being as definedabove; or

(iv)

w₂ and w₅ are hydrogen, w₃ is dialkylaminoalkyl-(N-methyl)aminocarbonyl##STR44## and w₄ is chloro; ALK and ALK' being as defined above;

or

(v)

w₃ and w₄ are hydrogen

w₂ is chloro, (C₁ -C₄)alkoxy or (C₁ -C₄)alkyl

w₅ is

(v1) dialkylaminoalkyl(N-methyl)aminocarbonyl ##STR45## (v2)dialkylaminoalkylcarbonylamino ##STR46## ALK and ALK' being as definedabove; their internal salts and their pharmaceutically acceptable salts,their quaternary ammonium salts and their solvates.

A preferred group of compounds according to the invention consists ofthe compounds of formula: ##STR47## in which: R₁, R₂ and R₃ are asdefined above for (I);

R_(4y) represents hydrogen, a (C₁ -C₄)alkyl group, an allyl or acyclopropylmethyl; and

the group --NH--AA_(y) --(OH) represents either a residue selected fromthe residue of 2-aminoadamantane-2-carboxylic acid, of(S)-∝-aminocyclohexaneacetic acid and of 9-aminobicyclo3.3.1!-nonane-9-carboxylic acid, or the residue of2-aminonorbornane-2-carboxylic acid;

their salts and their quaternary ammonium salts formed with acyclic orcyclic tertiary amines and their solvates.

Among the compounds of formula (Iy) as defined above, preference isgiven to those in which:

R₁, as defined for (I), is at position 4 or 5;

R₂ is at position 2 and represents a group chosen from: hydrogen, a (C₁-C₆)alkyl, a (C₃ -C₈)cycloalkyl, a (C₃ -C₈)cycloalkylmethyl, a (C₁-C₆)alkoxy, a (C₃ -C₈)cycloalkyloxy, a chlorine, a trifluoromethyl;

R₃ is at position 3 and represents hydrogen, a (C₁ -C₆)alkyl, a (C₃-C₈)cycloalkyl, a (C₃ -C₈)cycloalkylmethyl;

or R₂ and R₃ together constitute a trimethylene, a tetramethylene or apentamethylene;

their salts and their quaternary ammonium salts formed with acyclic orcyclic tertiary amines and their solvates.

In particular, preference is given to the compounds of formula (Iy'):##STR48## in which: R₁, R₂ and R₃ represent, respectively, R_(1p),R_(2p) and R_(3p) as defined above for (Ip);

R'_(4y) represents a (C₁ -C₄)alkyl or cyclopropylmethyl group; and

the group --NH--AA'_(y) --(OH) represents the residue of2-aminoadamantane-2-carboxylic acid or of (S)-α-aminocyclohexaneaceticacid or of 2-aminonorbornane-2-carboxylic acid.

Among the compounds of formula (Iy') as defined above, preference isgiven to those in which:

R₁ represents R_(1p) as defined for (I) and is at position 4 or 5;

R₂ is at position 2 and represents a group chosen from: hydrogen, a (C₁-C₆)alkyl, a (C₃ -C₈)cycloalkyl, a (C₁ -C₆)alkoxy, a chlorine, atrifluoromethyl;

R₃ is at position 3 and represents hydrogen or a (C₁ -C₆)alkyl;

or R₂ and R₃ together constitute a trimethylene, a tetramethylene or apentamethylene; and their salts.

Very special preference is given to the compounds of formula: ##STR49##in which: R_(4y) and NH--AA_(y) (OH) are as defined above for (Iy);

R_(1x) is at position 4 or 5 and represents a group chosen from--T--CONR_(a) R_(b), --SO₂ NR_(a) R_(b), --T--NR₅ R₆, --N(R₇)COR_(e),--OR_(d), --N(R₇)SO₂ R'₇, --T--NR₂₇ R₂₈ ; the groups --T--, R_(a),R_(b), R_(d), R_(e), R₅, R₆, R₇, R'₇, R₂₇ and R₂₈ being as defined abovefor (I);

R_(2x) and R_(3x) each independently represent hydrogen; a (C₁-C₆)alkyl; a (C₃ -C₈)cycloalkyl; a (C₃ -C₈)cycloalkylmethyl;

on condition that R_(2x) and R_(3x) do not simultaneously representhydrogen;

or R_(2x) and R_(3x) together constitute a tetramethylene group;

their salts and their quaternary ammonium salts formed with acyclic orcyclic tertiary amines and their solvates.

Among the compounds of formula (Ix), preference is given to those offormula Ix' ##STR50## in which: R'_(4y) represents a (C₁ -C₄)alkyl orcyclopropylmethyl group and NH--AA'_(y) (OH) is as defined above for(Iy');

R'_(1x) represents a group chosen from --T--CONR_(a) R_(b), --SO₂ NR_(a)R_(b), --Y--NR₅ R₆, --N(R₇)COR_(e), --OR_(d) ; the groups --T--,--NR_(a) R_(b), R_(d), R_(e), R₅, R₆ and R₇ being as defined above for(Ip);

R'_(2x) represents a (C₁ -C₆)alkyl, a (C₃ -C₈)cycloalkyl;

R'_(3x) represents hydrogen or a (C₁ -C₆)alkyl;

or R'_(2x) and R'_(3x) together constitute a tetramethylene group;

and their salts.

Among the compounds of formula (Iy), a preferred group consists of thecompounds of formula: ##STR51## in which R₄ y, R_(1x) and NH--AA_(y)(OH) are as defined above; preferably represents R'_(4y), R_(1p) andNH--AA'y(OH) as defined for (Iy') their salts and their quaternaryammonium salts formed with acyclic or cyclic tertiary amines and theirsolvates.

The compounds of the following formula are chosen more especially:##STR52## in which: R_(1x), R_(2x) and R_(3x) are as defined above for(Ix) preferably R'_(1x), R'_(2x) and R'_(3x) as defined above for (Ix'),R'_(1x) preferably being at the para position;

their salts and their quaternary ammonium salts formed with acyclic orcyclic tertiary amines and their solvates.

Preferentially, the invention relates to 2- 5-(2,6-dimethoxyphenyl)-1-4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylicacid, its internal salt and its salts which are preferablypharmaceutically acceptable, and its solvates.

According to another of its aspects, the present invention relates to aprocess for the preparation of the substituted1-phenyl-3-pyrazole-carboxamides of formula (I) and their salts,characterized in that:

1) a functional derivative of a 1-phenyl-3-pyrazolecarboxylic acid offormula: ##STR53## in which R₁, R₂, R₃ and R₄ have the meanings givenabove for the compound of formula (I) and R'₁ represents a precursor ofR₁ chosen from nitro, amino, phthalimido, halo, hydroxyl, sulpho,hydroxy(C₁ -C₇)alkylene, cyano, carboxyl, (C₁ -C₄)alkoxycarbonyl andbenzyloxycarbonyl groups, is treated with an amino acid, optionallyprotected by protective groups which are customary in peptide synthesis,of formula:

    H--HN--AA(OH)                                              (III)

in which --NH--AA(OH) is as defined above for the compound of formula(I);

2) where appropriate, the functional acid derivative thereby obtained,of formula: ##STR54## is subjected to a subsequent treatment suitablefor converting the substituent R'₁, a precursor of R₁, to thesubstituent R₁ ;

3) if necessary, the compound thereby obtained in step 1) or in step 2)is deprotected to yield the corresponding free acid of formula (I);

4) where appropriate, a salt of the compound (I) thereby obtained or itsquaternary ammonium salt is prepared.

As a functional derivative of the substituted1-phenyl-3-pyrazolecarboxylic acid of formula (II) or (II'), it ispossible to use the acid chloride, the anhydride, a mixed anhydride, aC₁ -C₄ alkyl ester, an activated ester, for example the p-nitrophenylester, or the free acid appropriately activated, for example withN,N'-dicyclohexylcarbodiimide or withbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP).

The amino acids of formula (III) may be used either as they are, orafter prior protection of the carboxyl group with protective groupswhich are customary in peptide synthesis, as described, for example, inProtective Groups in Organic Chemistry, Ed. J. F. W. McOmie, PlenumPress, 1973, page 183, or in Protective Groups in Organic Synthesis, IIEd. J. F. W. Greene and P. G. M. Wuts, John Wiley & Sons, 1991, page224.

For this protection, the carboxyl group of the amino acid (III) may bequite simply esterified, for example in the form of the methyl, benzylor tert-butyl ester, the esterifying group then being removed by acid orbasic hydrolysis or by hydrogenolysis. Protection by esterification canbe used only when the group R₁ or R'₁ does not contain, for its partalso, either an ester group which must be preserved, as in the casewhere, for example, R₁ might represent a group O--Y--COOR₇ or --Y--COOR₇or --T--CONR₇ CHR₂₀ COOR₇ or --T--CONR₇ (CH₂)₄ CH(NH₂)CO₂ R₇ with R₇=alkyl, or, in any case, a group liable to be affected during theunblocking of the ester group. Protection of the carboxyl group of theamino acid (III) may also be performed by silylation, for example withbis-(trimethylsilyl)acetamide, it being possible for the said protectionto be performed in situ. The silyl ester of the compound (I) is thenreadily removed during the isolation of the final product by simpleacidification, hydrolysis or exchange with an alcohol.

Thus, in step 1) of the process, the chloride of a1-phenyl-3-pyrazolecarboxylic acid, obtained by reacting thionylchloride with an acid of formula (II) or (II'), may be reacted with anamino acid of formula (III), in a solvent such as acetonitrile, THF, DMFor DCM, under an inert atmosphere, at room temperature, for a timebetween a few hours and a few days, in the presence of a base such aspyridine, sodium hydroxide or triethylamine.

A variant of step 1) consists in preparing the acid chloride or themixed anhydride of a 1-phenyl-3-pyrazolecarboxylic acid by reactingisobutyl or ethyl chloroformate with an acid of formula (II) or (II'),in the presence of a base such as triethylamine, and in reacting it withan N,O-bis(trimethylsilyl) derivative of an amino acid of formula (III),obtained by reacting bis(trimethylsilyl)acetamide or1,3-bis(trimethyl-silyl)urea or bis(trifluoromethylsilyl)acetamide withan amino acid of formula (III), in solvents such as acetonitrile andDCM, under an inert atmosphere, and for a time between 1 hour and a fewdays, at a temperature between room temperature and the refluxingtemperature of the solvent.

Another variant to the procedure of step 1) consists in reacting themixed anhydride of a 1-phenyl-3-pyrazolecarboxylic acid of formula (II)or (II') with an amino acid of formula (III), in a solvent such as DCM,under an inert atmosphere, at room temperature, for a time between 1 dayand a few days, in the presence of a base such as triethylamine.

When the compound of formula (I) possesses a basic function and isobtained in the form of a free base, salification is performed bytreatment with the chosen acid in an organic or aqueous solvent. Bytreatment of the free base, dissolved, for example, in an alcohol suchas isopropanol, with a solution of the chosen acid in the same solvent,the corresponding salt is obtained, which salt is isolated according tostandard techniques. Thus, for example, the hydrochloride, hydrobromide,sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulphonate,methyl sulphate, oxalate, maleate, fumarate or 2-naphthalene-sulphonateis prepared.

When the compound of formula (I) possesses a basic function and isisolated in the form of one of its salts, for example the hydrochlorideor oxalate, the free base may be prepared by neutralization of the saidsalt with an inorganic or organic base such as sodium hydroxide ortriethylamine, or with an alkali metal carbonate or bicarbonate such assodium or potassium carbonate or bicarbonate.

When the product of formula (I) is obtained in acid form, it may beconverted to a metal salt, in particular an alkali metal salt such asthe sodium salt or an alkaline-earth metal salt such as the calciumsalt, according to standard processes.

The compounds of formula (I) or (I') can under-go a dehydration in thepresence of an anhydride, for example acetic anhydride, to form anoxazolone derivative of formula: ##STR55## in which R₁, R'₁, R₂, R₃, R₄,X_(a) and X'_(a) have the meanings given above for (I) and R'₁represents a precursor of R₁ as defined above.

These compounds are new and constitute a further aspect of theinvention.

Among the compounds of formula (Ic) and (I'c), preference is given tothose for which X_(a) and X'_(a), together with the carbon atom to whichthey are attached, constitute an adamantane ring system or a bicyclo3.3.1!nonane, or alternatively X_(a) is hydrogen and X'_(a) represents acyclohexane.

From a compound of formula (I'c) or (Ic), a compound of formula (I) or(I') is prepared again by hydrolysis in an acid medium or in a basicmedium, for example in the presence of an alkali metal salt such aspotassium tert-butylate.

The intermediate preparation of a compound of formula (Ic) may be usefulto permit the purification of a compound of formula (I). Moreover, theintermediate preparation of a compound of formula (I'c) may be useful topermit the conversion of a substituent R'₁ to another substituent R'₁ orR₁, the acid function of the group NHAA(OH) being protected in theoxazolone group.

The substituted 1-phenyl-3-pyrazolecarboxylic acids of the formula:##STR56## in which R₁, R₂, R₃, and R₄ have the definitions given abovefor the compounds (I) and R'₁ represents a precursor of R₁ chosen formhalo, nitro, amino, phthalimido, hydroxyl, hydroxy(C₁ -C₇)alkylene,sulpho, cyano, carboxyl, (C₁ -C₄)alkoxycarbonyl and benzyloxycarbonylgroups, as well as their functional derivatives of the acid function,are key intermediates in the preparation of the compounds of formula(I). When R'₁ is other than carboxyl or halo, the compounds of formula(II) and (II') are new, and they constitute a further aspect of thepresent invention.

The acids of formulae (II) and (II'), the chlorides of the acids offormulae (II) and (II'), the C₁ -C₄ alkyl esters of the acids offormulae (II) and (II'), which can also be precursors of the said acids(in particular the methyl, ethyl and tert-butyl esters), and the mixedanhydride of the acids of formulae (II) and (II') with isobutyl or ethylchloroformate are especially preferred intermediate products.

The process for preparing the compounds (II) or (II') via the esters(IIa) or (II'a) is represented by the following scheme: ##STR57## M: Na,K Alk: Me, Et

Alk': (C₁ -C₄)alkyl

In the first step a), a strong base such as a metal alcoholate isreacted with a ketone of formula 1 in which R₄ is as defined above, andthen (step b) an equimolar amount of ethyl oxalate in an alkanol suchas, for example, methanol or ethanol is reacted according to L. Claisen,Ber., 1909, 42, 59. After precipitation in an ether such as ethyl etheror isopropyl ether, the enolates 2 are separated by filtration. It isalso possible to prepare a lithium enolate according to W. V. Murray etal., J. Heterocyclic Chem., 1989, 26, 1389.

The metal enolate 2 thereby prepared and an excess of phenylhydrazinederivative 3, or of a salt of the latter, are then heated to reflux ofacetic acid (step c) to obtain the esters IIa or II'a.

On saponification of the esters IIa or II'a by the action of an alkalineagent such as, for example, potassium hydroxide, sodium hydroxide orlithium hydroxide, followed by acidification, the acids II or II' areobtained (step d).

Among the compounds of formula 3, some are new and constitute a furthersubject of the present invention.

Thus, the compounds of formula: ##STR58## in which: R'₂ and R'₃ eachindependently represent a hydrogen, a (C₁ -C₆)alkyl, a (C₃-C₈)cycloalkyl, a (C₃ -C₈)cycloalkylmethyl;

or R'₂ and R'₃ together constitute a trimethylene, tetramethylene orpentamethylene group;

R_(y) is at position 4 or at position 5 and represents a group chosenfrom: cyano, carboxyl, (C₁ -C₄)alkoxycarbonyl, benzyloxycarbonyl,sulpho, (C₁ -C₄)alkylsulphonylamino, (C₁ -C₄)alkylphenylsulphonylamino,carbamoyl, (C₁ -C₄)alkylcarboxamido;

on condition that R'₂ and R'₃ do not simultaneously represent hydrogenand on condition that R'₂ is other than methyl when R_(y) is a sulphogroup; and their salts, are new and constitute a further subject of thepresent invention.

The phenylhydrazine derivatives (3) may be prepared according toHouben-Weyl, 1967, X-2, 169. For example, it is possible to carry outdiazotization of the corresponding phenylamine in the presence of sodiumnitrite, followed by reduction of the diazonium salt, for example by theaction of stannous chloride. When the phenyl contains anelectron-attracting substituent such as cyano or nitro, a fluorophenylderivative may also be substituted with hydrazine hydrate to obtain thecorresponding hydrazinophenyl derivative. The substituted phenylaminesare known or prepared by known methods. For example, the aminosulphonicacids are prepared according to Houben-Weyl, Methoden der OrganischenChemie. Verlag, 1955, vol. IX, 450.

The phenylhydrazine derivatives substituted with a group R₁ =YCO₂ R₇ areprepared from corresponding aniline or nitrophenyl derivatives.

The conversion of a compound of formula I' or respectively of formulaII' or of formula II'a in which the phenyl group is substituted with R'₁to a compound of formula I or respectively of formula II or of formulaIIa in which the phenyl group is substituted with R₁ is performed bystandard methods well known to a person skilled in the art.

The compounds of formula IIa or II'a in which R₁ or R'₁ represents acarboxyl or carboxy(C₁ -C₇)alkylene group enable compounds of formulaIIa in which R₁ represents a group --TCONR_(a) R_(b) to be prepared,with an amine HNR_(a) R_(b), by reaction of the acid chloride preparedin an intermediate step, or of any other activated derivative of theacid such as the mixed anhydrides, activated esters or derivativesobtained with 1,3-dicyclohexylcarbodiimide.

In the same way, the compounds of formula I' in which R'₁ represents agroup --TCOOH enable the compounds of formula I in which R₁ represents agroup --TCONR_(a) R_(b) to be prepared; the carboxylic acid function ofthe amino acid residue NHAA(OH) must then be protected in anintermediate step, for example by an ester group such as tert-butylester or by formation of the oxazolone derivative of formula (Ic).

From a compound of formula I or respectively Ic, or respectively from anester of formula IIa, or respectively from an alkali metal salt of anacid of formula II, in which compounds the substituent R₁ is a groupTCONH(CH₂)_(s) CR₇ R₈ (CH₂)_(t) NR₅ R₆, a compound of formula I orrespectively of formula Ic or respectively of formula IIa, orrespectively an alkali metal salt of acid of formula II, in whichcompounds the substituent R₁ is a group TCONR₉ (CH₂)_(s) CR₇ R₈(CH₂)_(t) NR₅ R₆, may be prepared by the action of an iodide of formulaR₉ I.

The compounds of formula IIa or respectively II or respectively Ic inwhich R₁ represents a carboxy-(C₁ -C₇)alkylene group enable thecompounds of formula IIa or respectively II or respectively I in whichR₁ represents a group --TCONR₇ R_(c) to be prepared by reacting the acidchloride prepared in an intermediate step with a compound NHR₇ R_(c),that is to say with a compound of formula NHR₇ XOR₇ or a compound offormula HNR₇ CHR₂₀ CO₂ R₇ or a compound of formula HNR₇ (CH₂)₄CH--(NHPro)CO₂ R₇ in which Pro represents a protecting group of theamine function used traditionally in peptide chemistry, for exampletert-butoxycarbonyl or benzyloxycarbonyl.

By reacting the compounds of formula I in which R₁ represents a --CH₂CONH₂ group with sodium peroxide, the compounds of formula I in which R₁represents a carboxymethyl group are obtained. By reducing the compoundsof formula I in which R₁ represents a --CH₂ CN group, for example byhydrogenation in the presence of a catalyst such as Raney® nickel, thecompounds of formula I in which R₁ represents a --CH₂ CH₂ NH₂ group areobtained. The latter compounds enable compounds of formula I in which R₁represents a group --CH₂ CH₂ NR₅ R₆, a group --CH₂ CH₂ N(R₇)COR_(e) or agroup --CH₂ CH₂ N(R₇)SO₂ R'₇ to be prepared by methods known to a personskilled in the art

Similarly, the compounds of formula (I) in which R₁ represents a group--T'--CN, T' being a direct bond or a (C₁ -C₆)alkylene, enable compoundsof formula I to be prepared in which R₁ represents a group --T'--CH₂NH₂, and then compounds of formula I in which R₁ is a group --T'--CH₂NR₅ R₆, a group --T'--CH₂ N(R₇)COR_(e) or a group --T'--CH₂ N(R₇)SO₂R'₇.

The catalytic reduction may be carried out according to CatalyticHydrogenation, R. L. Augustine-Marcel Dekker, 1967, 96-97; it may beapplied to the compounds of formula I in which R₂ and R₃ are other thana nitro or a cyano and R₄ is other than a (C₃ -C₄)alkenyl. Thesubstitution of the amino group may be performed by different processesdescribed, for example, in Catalytic Hydrogenation, R. L. Augustine-M.Dekker, 1965, 102-113, and Catalytic Hydrogenation over Platinum Metals,P. N. Rylander--Academic Press, 1967, 291. Thus, for example, theaddition of an aldehyde of formula R_(V) CHO to an amino group yields animine group which, on catalytic hydrogenation, is converted to secondaryamine --NHCH₂ R_(V) in which R_(V) represents a hydrogen or a (C₁-C₃)alkyl. The addition of a ketone of formula RCOR' yields an amine--NHCHRR' in which --CHRR' represents a group R₅, and R₆ is hydrogen.The addition of a (C₁ -C₄)alkyl halide also enables an amino groupsubstituted with one or two (C₁ -C₄)alkyls to be prepared. The additionof a suitable dihalide enables compounds to be prepared in which R₅ andR₆, together with the nitrogen atom to which they are attached,constitute a heterocycle chosen from pyrrolidine, piperidine,morpholine, thiomorpholine and piperazine substituted at position 4 withR₉, aziridine, azetidine and perhydroazepine.

The compounds of formula IIa in which R₁ represents a group T--NHSO₂ R'₇enable compounds of formula II'a in which R₁ represents a groupT--N(XNR₅ R₆)SO₂ R'₇ to be prepared by the action of a halide of formulaHalXNR₅ R₆. In an acid medium, compounds of formula II in which R₁ is agroup TNHXNR₅ R₆ which represents TNHR₂₈, may then be prepared. Toobtain the compounds of formula I in which R₁ represents a group TNR₂₇R₂₈, substitution of the nitrogen is performed by known methods, eitheron a compound of formula II or on a compound of formula I.

The compounds of formula II'a, or respectively the compounds of formulaII' or the compounds of formula I', in which R'₁ represents a nitrogroup may be converted to compounds of formula II'a, or respectively offormula II' or of formula I', in which R'₁ is an amino group; then, byknown methods, the compounds of formula IIa, or respectively of formulaII or of formula I, in which R₁ represents a group --N(R₇)COR_(e) or NR₅R₆ are prepared.

The compounds of formula II'a, or respectively of formula II' or offormula I', in which R'₁ is an amino group also enable compounds offormula II'a, or respectively of formula II' or of formula I', in whichR'₁ represents a hydroxyl group to be prepared; then, by known methods,the compounds of formula IIa, or respectively of formula II or offormula I, in which R₁ represents a group --OR_(d) are prepared.

From the compounds of formula II'a in which R'₁ is a group --Y--OH,compounds of formula II'a in which R'₁ is a group --Y--C₁ may beprepared by the action of hydrochloric acid or thionyl chloride; by theaction of a sulphonic acid derivative on these same compounds bearingthe substituent --Y--OH, compounds of the formula II'a in which R'₁ isthe group --Y--OSO₂ W, W representing a methyl, a trifluoromethyl or atolyl, may be prepared. The action of an amine NHR₅ R₆ on compounds offormula II'a substituted with a group --Y--C₁ or a group --Y--O--SO₂ Wenables compounds of formula IIa in which R₁ represents a group --Y--NR₅R₆ to be prepared.

When R₂ represents a nitro or cyano and R₃ represents hydrogen, theaction of a compound R_(d) OH in a basic medium on a compound of formulaII'a, or respectively of formula II' or respectively of formula I', inwhich R'₁ is a halogen at the ortho or para position with respect to R₂enables compounds of formula IIa, or respectively of formula II orrespectively of formula I, in which R₁ is a group --OR_(d) to beprepared.

When R₂ and R₃ are other than a halogen atom, a compound of formula IIa,or respectively of formula II or respectively of formula I, in which R₁is a cyano may also be prepared from a compound of formula II'a, orrespectively of formula II' or respectively of formula I', in which R'₁is a halogen, by the action of a cyanide derivative, for example thecuprous cyanide.

The compounds of formula I in which R₁ is a cyano group enable thecompounds of formula I in which R₁ is a carbamoyl group to be preparedby reaction with hydrogen peroxide in the presence of a base such assodium hydroxide. In the same way, the compounds of formula II in whichR₁ is a carbamoyl group are prepared from the compounds of formula IIain which R₁ is a cyano group.

The compounds of formula I in which R₁ is a cyano group also enable thecompounds of formula I in which R₁ represents a --C(NH₂)═NOH group or agroup --C(NH₂)═NO(CH₂)_(r) NR₅ R₆ to be prepared by reaction withhydroxylamine, where appropriate O-substituted with --(CH₂)_(q) NR₅ R₆,in the presence of a base such as potassium carbonate.

From the compounds of formula IIa, or respectively of formula II orrespectively of formula I, in which R₁ represents a C(NH₂)═NOH group,the compounds of formula IIa, or respectively of formula II orrespectively of formula I, in which R₁ represents C(═NOH)NH(CH₂)_(r) NR₅R₆ are prepared according to Chem. Ber., 1970, 103, 2330-2335.

By reducing the compounds of formula IIa, or respectively of formula IIor of formula I, in which R₁ represents a cyano group, for example byhydrogenation in the presence of a catalyst such as platinum oxide,followed by reaction with an acid chloride or a suitable anhydride orrespectively with a sulphonyl chloride, the compounds of formula IIa, orrespectively of formula II or of formula I, in which R₁ represents agroup --CH₂ NHCOR₁₆ or respectively --CH₂ NHSO₂ R'₇ are obtained.Similarly, the compounds of formula IIa, or respectively of formula IIor of formula I, in which R₁ represents a group --CH₂ N(R₇)COR₁₆ or agroup --CH₂ N(R₇)SO₂ R'₇, with R₇ other than hydrogen, are obtained byperforming an alkylation reaction on the amide obtained in anintermediate step.

When the hydrogenation of a compound of formula II'a or respectively offormula II' or respectively of formula I', in which R'₁ represents acyano group is performed in the presence of an amine HNR₅ R₆, a compoundof formula I or respectively of formula II or respectively of formulaIIa, in which R₁ represents a group CH₂ NR₅ R₆ is obtained.

The reaction of the compounds of formula I in which R₁ represents agroup TCN or --T--CON(R₇)(CH₂)_(q) CN or a group --T--N(R₇)CO(CH₂)_(q)CN or a group --SO₂ N(R₇)(CH₂)_(q) CN with hydrochloric acid inalcoholic solution AlkOH enables the corresponding imidate of formula:

--T--C(═NH)OAlk, --T--CONR₇ (CH₂)_(q) C(═NH)OAlk,--T--N(R₇)CO--(CH₂)_(q) C(═NH)OAlk or --SO₂ N(R₇)(CH₂)_(q) C(═NH)OAlk inwhich Alk is a (C₁ -C₄)alkyl to be obtained in an intermediate step.

If the imidate is reacted with an equimolar amount of amine HNR₁₂ R₁₃,the compounds of formula I in which R₁ represents:

a group --TC(NR₁₂ R₁₃)═NR₁₄

a group --TCON(R₇)(CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄ or

a group --TN(R₇)CO(CH₂)_(q) C(NR₁₂ R₁₃)═N--R₁₄ or

a group --SO₂ N(R₇)(CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄ with R₁₄ ═H are obtained.

If the imidate is reacted with an excess of amine NH₂ R₁₃, in which R₁₃is other than hydrogen, the compounds of formula I in which R₁represents:

a group --TC(NHR₁₃)═NR₁₃

a group --TCON(R₇)(CH₂)_(q) C(NHR₁₃)═N--R₁₃ or

a group --TN(R₇)CO(CH₂)_(q) C(NHR₁₃)═NR₁₃ or

a group --SO₂ N(R₇) (CH₂)_(q) C(NHR₁₃)═NR₁₃ are obtained.

If the imidate is reacted with a diamine of formula H₂ N--Z--NHR₁₂, thecompounds of formula I in which R₁ represents:

a group --TC(NR₁₂ R₁₃)═NR₁₄

a group --TCON(R₇)(CH₂)_(q) C(NR₁₂ R₁₃)═N--R₁₄ or

a group --TN(R₇)CO(CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄ or

a group --SO₂ N(R₇)(CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄, in which R₁₃ and R₁₄together constitute a C₂ -C₆ alkylene group and R₁₂ represents ahydrogen or a (C₁ -C₄)alkyl, are obtained.

A compound of formula (I) in which R₁ contains an optionally substitutedamidino radical may also be prepared according to the methods describedin The chemistry of amidines and imidates, Saul Patai, 1975, John Wileyand Sons.

From the compounds of formula I, or respectively of formula II or IIa,in which R₁ represents a group --TCONR₇ (CH₂)_(q) CN, compounds offormula I, or respectively II or IIa, in which R₁ represents a group--TCONR₇ (CH₂)_(q) CONH₂ or a group --TCONR₇ (CH₂)_(q) CO₂ R₇ areprepared by known reactions.

When R'₁ =SO₃ H, a compound II'a in which R'₁ ═SO₂ Cl is prepared andthen converted to another compound IIa in which R₁ is an aminosulphonylgroup, optionally substituted, by the action of a suitable amine HNR_(a)R_(b).

The compounds of formula I comprising a quaternary ammonium group areobtained from the corresponding amino compounds by the action of acompound of formula QR₂₄ in which Q can form anion, for example aniodide.

The amino acids of formula III include, for example, glycine, alanine,leucine, norleucine, isoleucine, valine, 1-adamantylglycine,2-adamantylglycine, cyclopropylglycine, cyclopentylglycine,cyclohexylglycine, cycloheptylglycine, 1-aminocyclopropanecarboxylicacid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylicacid, 1-aminocyclohexanecarboxylic acid, 1-aminocycloheptanecarboxylicacid, 1-amino-4-methylcyclohexanecarboxylic acid,2-amino-2-adamantanecarboxylic acid, 2-aminobicyclo 3.2.1!octane-2-carboxylic acid, 9-aminobicyclo 3.3.1!nonane-9-carboxylicacid and 2-aminobicyclo 2.2.1!heptane-2-carboxylic or2-amino-2-norbornanecarboxylic acid.

The amino acids of formula III are commercial products or may be veryreadily prepared according to standard methods. In particular, thenon-commercial amino acids (III) are prepared according to the Streckersynthesis, Ann, 1850, 75, 27 or according to the synthesis of H. T.Bucherer et al., J. Pract. Chem., 1934, 141, 5, followed by a hydrolysisto yield the amino acids; for example, 2-amino-2-adamantanecarboxylicacid and 9-aminobicyclo 3.3.1!nonane-9-carboxylic acid are preparedaccording to H. T. Nagasawa et al., J. Med. Chem., 1973, 16, (7), 823.

α-Amino-1-adamantylacetic and α-amino-2-adamantylacetic acids areprepared according to B. Gaspert et al., Croatica Chemica Acta, 1976, 48(2), 169-178.

2-Amino-2-norbornanecarboxylic acid is prepared according to H. S. Tageret al., J. Am. Chem. Soc., 1972, 94, 968.

α-Aminocycloalkylcarboxylic acids are prepared according to J. W. Tsanget al., J. Med. Chem., 1984, 27, 1663.

(R)- and (S)-cyclopentylglycines are prepared according to EuropeanPatent Application EP 477,049.

(R)- and (S)-cyclohexylglycines are prepared according to Rudman et al.,J. Am. Chem. Soc., 1952, 74, 551.

(R)- and (S)-cyclohexylglycines may also be prepared by catalytichydrogenation of (R)- and (S)-phenylglycines.

α-Aminocycloalkylcarboxylic acids of R or S configuration may also beprepared by stereospecific enzymatic hydrolysis of the correspondingracemic N-acetyl derivatives according to J. Hill et al., J. Org. Chem.,1965, 1321.

The compounds of formula (I) and their salts possess a very greataffinity for human neurotensin receptors in the tests described by D.Gully et al. in Proc. Natl. Acad. Sci. USA, 1993, 90, 65-69.

The compounds of formula I and their salts were studied in vivo. Workingaccording to the technique described by M. Poncelet et al. in NaunynSchmiedberg's Arch. Pharmacol., 1994, 60, 349-357, it is observed that acompound according to the invention, administered orally, antagonizesthe contralateral pivoting induced by unilateral intrastriatal injectionof neurotensin in mice.

Moreover, working according to the technique described by D. Nisato etal. in Life Sciences, 1994, 54, 7, 95-100, it is found that a compoundaccording to the invention, administered intravenously, inhibits theincrease in blood pressure induced by intravenous injection ofneurotensin in guinea pigs.

The compounds described in Patent EP 0,477,049 exhibit a lower activityin these tests than that of the compounds according to the presentinvention.

The compounds of the present invention are of low toxicity; inparticular, their acute toxicity is compatible with their use as amedicinal product. For such a use, an effective amount of a compound offormula I, or of one of its pharmaceutically acceptable salts, isadministered to mammals for the treatment of neurotensin-dependentpathologies. Thus, the compounds of the present invention may be usedfor the treatment of neuropsychiatric disorders, especially thoseassociated with a dysfunction of the dopaminergic systems, for examplepsychoses, more especially schizophrenia, and diseases of movement suchas Parkinson's disease (D. R. Handrich et al., Brain Research, 1982,231, 216-221 and C. B. Nemeroff, Biological Psychiatry, 1980, 15 (2),283-302). They may be used to diagnose and/or treat malignant neoplasticdiseases, for example human meningiomas which are not surgicallyaccessible (P. Mailleux, Peptides, 1990, 11, 1245-1253), cancers of theprostate (I. Sehgal et al., Proc. Nat. Acad. Sci., 1994, 91, 4673-4677)and small cell cancers of the lung (T. Sethi et al., Cancer Res., 1991,51, 3621-3623). They may be used in the treatment of motor, secretory,ulcerous and/or tumoral gastro-intestinal disorders (review by A.Shulkes in "Gut Peptides: Biochemistry and Physiology, Ed. J. Waish andG. J. Dockray, 1994"). Thus, the compounds I according to the inventionmay be used in the treatment of complaints such as: irritable bowelsyndrome, diarrhoea, colitis, ulcers, tumours of the gastro-intestinaltract, dyspepsia, pancreatitis and oesophagitis. They may also be ofvalue as modulators of food intake (Beck, B. Metabolism, 1995, 44,972-975). The compounds according to the invention may be indicated asdiuretics, as well in the case of cardiovascular disorders, and also inthe case of pathologies associated with a histamine release such asinflammatory processes (D. E. Cochrane et al., Faseb J., 1994, 8, 7,1195). These compounds may also be useful for treating certain disorderscaused by stress, such as migraines, neurogenic pruritus andinterstitial cystitis (Theoharides T. C. et al., Endocrinol., 1995, 136,5745-5750). The compounds of the present invention may also be of valuein analgesia, by acting on the effects of morphine (M. O. Urban, J.Pharm. Exp. Ther., 1993, 265, 2, 580-586).

Thus, the subject of the present invention, according to another of itsaspects, is pharmaceutical compositions containing as active principlesthe compounds of formula I or their possible pharmaceutially acceptablesalts.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, transdermal orrectal administration, the active principles may be adminisered, insingle-dose administration forms, as a mixture or with standardpharmaceutical vehicles, to animals and human beings. Suitablesingle-dose administration forms comprise forms for oral administration,such as tablets, gelatin capsules, powders, granules and oral solutionsor suspensions, forms for administration by inhalation, forms forsublingual and buccal administration, forms for subcutaneous,transcutaneous, intramuscular or intravenous administration and formsfor rectal administration.

In order to obtain the desired effect, the dose of active principle canvary between 0.5 and 1000 mg per day, and preferably between 2 and 500mg.

Each single dose can contain from 0.5 to 250 mg of active principle, andpreferably from 1 to 125 mg, in combination with a pharmaceuticalvehicle. This single dose can be administered 1 to 4 times daily.

When a solid composition is prepared in the form of tablets, the activeprinciple is mixed with a pharmaceutical vehicle such as gelatin,starch, lactose, magnesium stearate, talc, gum arabic or the like. It ispossible to coat the tablets with sucrose or with other suitablesubstances, or they may alternatively be treated in such a way as tohave a sustained or delayed activity and to release continuously apredetermined amount of active principle.

A gelatin capsule preparation is obtained by mixing the active principlewith a diluent and pouring the mixture obtained into soft or hardgelatin capsules.

A preparation in syrup or elixir form can contain the active principletogether with a sweetener, preferably a zero-calorie sweetener, andmethylparaben and propylparaben as antiseptic, as well as an agentimparting flavour and a suitable colorant.

The water-dispersible powders or granules can contain the activeprinciple mixed with dispersing agents or wetting agents, or suspendingagents such as polyvinylpyrrolidone and the like, as well as withsweeteners or flavour correctors.

For rectal administration, suppositories are employed, which areprepared with binding agents melting at rectal temperature, for examplecocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspenions, isotonic salinesolutions or sterile and injectable solutions are used, which containpharmacologically compatible dispersing and/or wetting agents, forexample propylene glycol or butylene glycol.

The active principle may also be formulated in the form ofmicrocapsules, optionally with one or more vehicles or additives.

To improve the solubility of the products of the invention, thecompounds of formula I or their pharmaceutically acceptable salts mayalso be presented in the form of complexes with cyclodextrins.

In the description and in the examples, the following abbreviations areused:

MeOH: methanol

EtOH: ethanol

Ether: ethyl ether

Ethereal hydrogen chloride=a saturated solution of hydrochloric acid inether

Ethanolic hydrogen chloride=a saturated solution of hydrochloric acid inethanol

Iso ether: isopropyl ether

AcOEt: ethyl acetate

MeCN: acetonitrile

DCM: dichloromethane

DMF: dimethylformamide

DMSO: dimethyl sulphoxide

THF: tetrahydrofuran

HCl: hydrochloric acid

H₂ SO₄ : sulphuric acid

AcOH: acetic acid

TFA: trifluoroacetic acid

NaOH: sodium hydroxide

KOH: potassium hydroxide

LiOH: lithium hydroxide

NH₄ OH: ammonium hydroxide

Na₂ SO₄ : sodium sulphate

NaHCO₃ : sodium hydrogen carbonate

NaHSO₃ : sodium hydrogen sulphite

Na₂ CO₃ : sodium carbonate

K₂ CO₃ : potassium carbonate

P₂ O₅ : phosphorus pentoxide

NBS: N-bromosuccinimide

POCl₃ : phosphorus oxychloride

NaNO₂ : sodium nitrite

SOCl₂ : thionyl chloride

SnCl₂ : stannous chloride

CuCN: suprous cyanide

Me, MeO: methyl, methoxy

Et: ethyl

iPr: isopropyl

iBu: isobutyl

n-Bu: n-butyl

t-Bu: tert-butyl

Bz: benzyl

m.p.: melting point

RT: room temperature

Silica H: silica gel 60 H marketed by MERCK (DARMSTADT )

NMR: nuclear magnetic resonance

Except where otherwise stated, NMR spectra are recorded at 200 MHz inDMSO-d₆. Chemical shifts δ are expressed in parts per million (ppm)relative to tetramethylsilane as internal reference.

s: singlet

bs: broad singlet

ss: split singlet

d: doublet

dd: doublet of doublet

t: triplet

qr: quartet

qt: quintet

sp: septet

u.c.: unresolved complex

mt: multiplet

PREPARATION 1.1

Methyl 4-(2,6-dimethoxyphenyl)-4-oxido-2-oxo-3-butenoate sodium salt:Compound A.

A solution of 100 g of 2,6-dimethoxyacetophenone and 7.5 ml of ethyloxalate in 520 ml of anhydrous MeOH is added slowly to a solution ofsodium methylate prepared from 12.7 g of sodium and 285 ml of anhydrousMeOH. The reaction mixture is heated to reflux for 7 hours and leftovernight at RT. It is poured into 2 litres of isopropyl ether and leftstirring for 15 minutes. The expected product is obtained by filtration,washing with isopropyl ether and drying under vacuum, m=120 g, m.p.=178°C.

Ethyl 4-(2,6-dimethoxyphenyl)-4-oxido-2-oxo-3-butenoate potassium salt:Compound A₁.

A solution of 13.4 g of 95% potassium tertbutylate in 72 ml of ethanolis added over 6 minutes to a solution, stirred and heated to 50° C., of18 g of 2,6-dimethoxyacetophenone in 54 ml of ethanol. The mixture isheated to reflux, 16.3 ml of ethyl oxalate are added over 9 minutes andrefluxing is continued for 1 hour. 40 ml of ethanol are then distilledoff and the mixture is allowed to cool with stirring for two and a halfhours. The mixture is filtered, and the precipitate is washed with 40 mlof ethanol and dried under vacuum at 60° C. for 17 hours to obtain 31 gof expected product.

NMR: 1.2:t:3H; 3.6:s:6H; 4:mt:2H; 5.5:s:1H; 6.55:d:2H; 7.1:t:1H.

PREPARATION 1.2

Ethyl 4-2-(cyclopropylmethyloxy)-6-methoxy-phenyl!-4-oxido-2-oxo-3-butenoatesodium salt.

A) 2-(Cyclopropylmethyloxy)-6-methoxyacetophenone.

32.7 ml of a 50% solution of caesium hydroxide in water are added at RTto a solution of 26 g of 2-hydroxy-6-methoxyacetophenone in 400 ml of2-propanol, and the mixture is left stirring for 15 minutes at RT. It isconcentrated under vacuum, the residue is taken up with 2-propanol, themixture is concentrated under vacuum, toluene is then added and theresulting mixture is concentrated under vacuum. The residue is dissolvedin 200 ml of DMF, 25.3 g of cyclopropylmethyl bromide are added and themixture is heated to 80° C. for 2 hours 30 minutes. It is concentratedunder vacuum, the residue is taken up with water, the mixture isextracted with AcOEt, the organic phase is washed with a saturated NaClsolution and dried over Na₂ SO₄ and the solvent is evaporated off undervacuum. 32.7 g of the expected product are obtained.

B) Ethyl 4-2-(cyclopropylmethyloxy)-6-methoxy-phenyl!-4-oxido-2-oxo-3-butenoatesodium salt.

A solution of 32.6 g of the compound obtained in the preceding step and20.1 ml of diethyl oxalate in 100 ml of EtOH is added slowly to asolution of sodium ethylate prepared from 3.4 g of sodium and 60 ml ofEtOH. The mixture is heated overnight at 60° C., allowed to cool to RTand concentrated under vacuum. The residue is taken up with pentane, andthe precipitate formed is drained, washed with pentane and dried undervacuum. 41.2 g of the expected product are obtained.

PREPARATIONS OF THE HYDRAZINES 3 PREPARATION 2.1

3-Isopropyl-4-hydrazinobenzoic acid hydrochloride.

A) 2-Isopropylacetanilide.

This compound is described in Bull. Soc. Chim., France, 1949, 144.

A mixture containing 300 ml of toluene and 31 ml of 2-isopropylanilineis cooled in ice, and 22 ml of acetic anhydride are added slowly. After40 minutes with stirring at RT, the reaction medium is evaporated andthe residue is then taken up with petroleum ether. The precipitateformed is drained. 35.9 g of the expected product are obtained aftercrystallization in petroleum ether, m.p.=81° C.

B) 4-Bromo-2-isopropylacetanilide.

This compound is described in J. Med. Chem., 1974, 17(2), 221.

A few drops of a solution of 10.1 ml of bromine in 180 ml of acetic acidare added slowly to a mixture containing 34.8 g of the compound obtainedin the preceding step in 250 ml of acetic acid, and the mixture is thenheated to 50° C.; after cooling, a few drops of the solution are addedagain and the mixture is heated to 50° C., this being continued untilthe addition is complete. The reaction medium is gradually heated toreflux and then allowed to return to RT over-night. The precipitateformed is filtered off and then added to a dilute solution of NaHSO₃.The product is filtered off again, rinsed with water and then dried overP₂ O₅. 27.4 g of the expected product are obtained, m.p.=134° C.

The compound of step B) may also be prepared according to the proceduredescribed below.

B') 4-Bromo-2-isopropylacetanilide.

A mixture is prepared containing 117.6 g of 2-isopropylacetanilide in330 ml of DMF, and 117.6 g of NBS in 330 ml of DMF are added over 25minutes. The mixture is left stirring at RT for 5 hours and then pouredinto 1.5 litres of water while cooling the reaction medium with ice. Theprecipitate formed is filtered off, rinsed with water and then dried at50° C. under vacuum. The filtrate is extracted with DCM (twice), washedwith water and then dried over Na₂ SO₄ to obtain a second fraction ofthe expected product. By combining the different purified fractions, 158g of the expected product are obtained, m.p.=134° C.

C) 4-Cyano-2-isopropylacetanilide.

A mixture containing 26.48 g of the product obtained in the precedingstep, 60 ml of DMF, 1 ml of water and 10.25 g of cuprous cyanide isstirred under reflux for 10 hours. After cooling, the mixture is pouredinto a solution of 50 g of sodium cyanide in 150 ml of water at 40° C.The precipitate formed is filtered off and rinsed several times withwater. 16.7 g of the expected product are obtained, m.p.=134° C.

D) 4-Cyano-2-isopropylaniline hydrochloride.

16.13 g of the compound obtained in the preceding step, 65 ml of 100%ethanol and 40 ml of 1N HCl are mixed, and the mixture is stirred underreflux for 19 hours. After one night at RT, 10% NaOH solution is addeduntil a pH of 10 is obtained. The reaction medium is extracted twicewith DCM, and the organic phase is dried over Na₂ SO₄ and concentratedunder vacuum. The residue is dissolved in ether and ethereal hydrogenchloride is added. The precipitate formed is filtered off and rinsedwith ether. 15.32 g of the expected product are obtained, which productcrystallizes in the Et₂ O/HCl mixture, m.p.=188° C.

E) 4-Amino-3-isopropylbenzoic acid hydrochloride.

This compound is described in J. Med. Chem., 1974, 17(2), 221.

A mixture containing 1 g of the compound obtained in the preceding step,2.86 g of ground potassium hydroxide, 6 ml of water and 0.5 ml ofdimethoxyethane is heated to reflux for 12 hours. After cooling,concentrated HCl is added until a pH of 1 is obtained, and the mixtureis then extracted twice with DCM; the organic phase is dried over Na₂SO₄ and concentrated. 0.96 g of the expected product is obtained,m.p.=128° C.

F) 3-Isopropyl-4-hydrazinobenzoic acid hydrochloride.

A mixture containing 0.96 g of the product obtained in the precedingstep, 22 ml of concentrated HCl and 20 ml of acetic acid is cooled to-5° C., 0.36 g of NaNO₂ in 4 ml of water is added and the mixture isthen left stirring at 0° C. for 1 hour 15 minutes. It is cooled to -10°C., and 3.73 g of stannous chloride dihydrate in 4 ml of concentratedHCl are added. The temperature is allowed to rise to 18° C., and theprecipitate formed is then filtered off and rinsed with 1 ml of diluteHCl. 0.96 g of the expected product is obtained after drying over P₂ O₅.

PREPARATION 2.1a

3-Isopropyl-4-hydrazinobenzoic acid hydrochloride may also be preparedaccording to the procedure described below.

A) 4-Bromo-2-isopropylacetanilide.

200 ml of acetic anhydride are added over 10 minutes to 300 ml of2-isopropylaniline while the temperature is maintained below 60° C.After 45 minutes of stirring at RT, a solution of one equivalent of NBSin 720 ml of DMF is added. After 2 hours of stirring, the mixture ispoured into 5.7 1 of water/AcOEt (2:1; v/v) mixture, settling is allowedto take place, and the organic phase is separated, dried over Na₂ SO₄and evaporated under vacuum. The residue is solidified in isopropylether and filtered off to obtain 367 g of the expected product.

B) 4-Cyano-2-isopropylacetanilide.

10.25 g of the product of step A and 1.2 equivalents of cuprous cyanidein 20 ml of DMF are heated to reflux for 6 hours. The mixture is cooledto 20° C. and poured into a mixture of 200 ml of AcOEt and 200 ml of 20%ammonium hydroxide. The organic phase is washed again with 50 ml of 20%ammonium hydroxide and then twice with saturated NaCl solution. Afterdrying over Na₂ SO₄, it is evaporated under vacuum, and the residue istreated with isopropyl ether, filtered off and dried at 40° C. undervacuum to obtain 6.15 g of the expected product.

The compound of step B may also be prepared according to the procedurebelow:

B') Argon is bubbled through a stirred mixture of 22.16 g of product ofstep A and 0.6 equivalent of zinc cyanide in 67 ml of anhydrous DMF. Themixture is heated to 80° C. and 2 g oftetrakis(triphenylphosphine)-palladium(O) are added while the mixture isprotected from light. After 3 hours of stirring at 80° C., the mixtureis allowed to cool to RT and 120 ml of 4% ammonium hydroxide and 200 mlof AcOEt are added, and the combined organic phases are washed againwith 4% ammonium hydroxide. They are dried over Na₂ SO₄ and evaporatedunder vacuum, and the residue is treated with isopropyl ether, filteredoff and dried under vacuum to obtain 15 g of the expected nitrile.

C) 4-Amino-3-isopropylbenzoic acid hydrochloride.

A mixture of 100 g of the product of step B with 500 ml of concentratedHCl and 500 ml of AcOH is heated to reflux for 10 hours. It isconcentrated under vacuum, and the precipitate is filtered off and driedunder vacuum to obtain 103.8 g of expected product.

D) 3-Isopropyl-4-hydrazinobenzoic acid hydrochloride.

A solution of 27.7 g of NaNO₂ in 250 ml of water is added slowly to amixture, cooled to -5° C., of 59 g of the product of step C with 1050 mlof AcOH and 1420 ml of concentrated HCl. After1 hour 20 minutes ofstirring at 0° C., the mixture is cooled to -10° C. and a solution of236 g of SnCl₂ ·2H₂ O in 250 ml of concentrated HCl is added. Thetemperature is allowed to rise to RT, and the precipitate is filteredoff, washed with concentrated HCl and dried under vacuum to obtain 56.36g of expected product.

PREPARATION 2

3-Isopropyl-4-hydrazinobenzenesulphonic acid hydrochloride.

A) 4-Amino-3-isopropylbenzenesulphonic acid.

5.7 ml of H₂ SO₄ are added to 10 ml of water, the mixture is heated to80° C. and 13.5 g of 2-isopropylaniline are then added. The water isevaporated off by heating under vacuum, and the temperature is thengradually raised over one and a half hours to reach 260° C. After 3hours with stirring and under vacuum at 260° C., the reaction medium isallowed to return to RT and to atmospheric pressure, and is then heatedfor 30 minutes in the presence of 15 ml of NaOH and 100 ml of water inorder to dissolve the reaction medium. The insoluble matter is filteredoff, and the mixture is cooled to 5° C. and then acidified to pH 1 byadding concentrated H₂ SO₄. The precipitate formed is filtered off,washed with 5 ml of cold water and dried to obtain 20 g of the expectedproduct.

NMR: 1.1:d:6H; 2.95:mt:1H; 6.85:d:1H; 7.45:dd:1H; 7.6:d:1H.

B) 3-Isopropyl-4-hydrazinobenzenesulphonic acid hydrochloride.

10 ml of ice and 3.2 g of NaNO₂ are added to a solution of 10 g of theproduct prepared in the preceding step in 10 ml of 30% NaOH and 20 ml ofwater. This solution is poured slowly into a solution of 30 ml ofconcentrated HCl in 20 ml of water at a temperature of between -5° C.and -15° C. The mixture is left stirring for one hour at thistemperature, and 26 g of stannous chloride dihydrate in 40 ml ofconcentrated HCl are then added at a temperature of between 0° C. and-5° C. After two and a half hours with stirring at RT, the productobtained is filtered off and then dried under vacuum in the presence ofP₂ O₅. 9.7 g of the expected product are thereby obtained.

NMR: 1.2:d:6H; 3.15:mt:1H; 6.8:d:1H:7.45:d:1H; 7.55:s:1H; 7.9:bs:1H;10:bs:3H.

PREPARATION 2.3

4-Hydrazino-5,6,7,8-tetrahydro-1-naphthalene-carboxylic acidhydrochloride.

A) 4-Amino-5,6,7,8-tetrahydro-1-naphthalene-carboxylic acid.

4-Nitro-5,6,7,8-tetrahydro-1-naphthalene-carboxylic acid is described inChem. Pharm. Bull., 1984, 32, 3968. The hydrogenation of 1.48 g of thisnitro derivative is performed in methanol in the presence of Raney®nickel. After 4 hours with stirring, the catalyst is filtered off, themixture is evaporated to dryness and the residue is taken up with etherand filtered off to obtain 1 g of the expected product. m.p.=180° C.(dec.).

B) 4-Hydrazino-5,6,7,8-tetrahydro-1-naphthalene-carboxylic acidhydrochloride.

A solution of 0.26 g of NaNO₂ in 1 ml of water is added to a solution,cooled to -5° C., of 0.73 g of4-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid in 10 ml ofconcentrated HCl. After one and a half hours of stirring at -5° C., asolution of 3.4 g of SnCl₂ ·2H₂ O in 34 ml of concentrated HCl is addedat -5° C. The mixture is stirred for 1 hour at RT and filtered, and theproduct is washed with concentrated HCl and dried under a stream of drynitrogen to obtain 0.67 g of the expected hydrazine.

PREPARATION 2.4

4-Hydrazino-5,6,7,8-tetrahydro-1-naphthalene-sulphonic acidhydrochloride.

A) 4-Amino-5,6,7,8-tetrahydro-1-naphthalene-sulphonic acid.

A hot suspension of 20 g of sulphamic acid in 40 ml ofN-methylpyrrolidone is added to a solution of 10 g of5,6,7,8-tetrahydronaphthylamine in 100 ml of 1,2-dichlorobenzene. Themixture is heated with stirring for 7 hours at 150° C. The product isfiltered off and washed with dichlorobenzene and then with toluene. Theprecipitate is resuspended in 70 ml of water and neutralized to pH 7with 5.5 ml of 30% sodium hydroxide. The insoluble matter is filteredoff and the aqueous phase is extracted with ether. The aqueous phase isadjusted to pH 5 by adding HCl, at 5° C.; the mixture is filtered, andthe residue is washed with water and dried to obtain 7.5 g of theexpected product.

B) 4-Hydrazino-5,6,7,8-tetrahydro-1-naphthalene-sulphonic acidhydrochloride.

1 g of NaNO₂ is added to a solution of 3 g of the acid obtained in stepA in 10 ml of water and 2 ml of 30% sodium hydroxide. This solution ispoured over 1 hour into 10 ml of concentrated HCl cooled to 5° C. Afterstirring for 3 hours at 5° C., a solution of 7.5 g of SnCl₂ ·2H₂ O in 15ml of concentrated HCl is added slowly while the temperature ismaintained at 5° C. The mixture is left stirring for one and a halfhours at RT and filtered, and the residue is dried under vacuum toobtain 2.86 g of the expected product.

NMR (D₂₀ --NaOD): 1.6:mt: 4H; 2.25:mt: 2H; 2.9:mt: 2H; 6.75:d: 1H;7.6:d: 1H.

PREPARATION 2.5

4-Hydrazino-3-methylbenzamide hydrochloride.

A) 4-Amino-3-methylbenzamide.

This product is prepared by catalytic hydrogenation of3-methyl-4-nitrobenzamide, m.p.=124° C.

B) 4-Hydrazino-3-methylbenzamide hydrochloride.

0.5 g of the compound of step A is dissolved in 10 ml of 1N HCl and 5 mlof concentrated HCl. The mixture is cooled to 0° C. and a solution of230 mg of NaNO₂ in 3 ml of water is added. After 15 minutes at -10° C.,a solution of 1.5 g of SnCl₂ ·2H₂ O in 5 ml of concentrated HCl isadded. After 1 hour the precipitate is filtered off and dried undervacuum over P₂ O₅ to obtain 390 mg of the expected product.

PREPARATION 2.6

2,3-Dimethyl-4-hydrazinobenzoic acid hydrochloride.

A solution of 1.87 g of NaNO₂ in 7 ml of water is added slowly to asolution, cooled to -5° C., of 4.5 g of 4-amino-2,3-dimethylbenzoic acidin 135 ml of concentrated HCl. After 2 hours of stirring at -5° C., asolution of 25 g of SnCl₂ ·2H₂ O in 250 ml of concentrated HCl is addedat -10° C., and the mixture is stirred for 30 minutes at -5° C. and then2 hours at RT. The mixture is filtered, and the precipitate is washedwith 5 ml of concentrated HCl and dried under a stream of dry nitrogenand then under vacuum to obtain 5.5 g of expected product.

NMR: 2.1:s:3H; 2.4:s:3H; 6.8:d:2H; 7.6:d:2H; 8.2:s:1H; 10:bs:2H.

PREPARATION 2.7

4-Hydrazino-3-methoxybenzoic acid hydrochloride.

A solution of 2.17 g of NaNO₂ in 40 ml of H₂ O is added slowly to asolution, cooled to 0° C., of 5 g of 4-amino-3-methoxybenzoic acid in 50ml of concentrated HCl. After 1 hour 15 minutes of stirring at 0° C.,the mixture is cooled to -10° C., and a solution of 23.6 g of SnCl₂ ·2H₂O in 20 ml of concentrated HCl and 20 ml of water is added over 30 min.After one and a half hours of stirring at -10° C., the mixture isfiltered, and the precipitate is washed with 50 ml of pentane to obtain,after drying, 6 g of expected product.

NMR: 3.8:s:3H; 7:d:1H; 7.4:s:1H; 7.5:dd:1H; 8:bs:1H; 10.6:bs:2H.

PREPARATION 2.8

2-Chloro-4-hydrazinobenzonitrile hydrochloride.

5 g of 4-amino-2-chlorobenzonitrile and 40 ml of concentrated HCl in 30ml of THF are mixed at -5° C.; 2.26 g of NaNO₂ in 30 ml of water areadded and the mixture is left stirring for 2 hours, 30 g of SnCl₂ ·2H₂ Oin 30 ml of concentrated HCl are then added and stirring is maintainedat -5° C. for 30 minutes.

After a return to RT, the insoluble matter is filtered off, NaCl isadded and the mixture is stirred again. The expected productcrystallizes with NaCl; it is taken up in ethanol while the NaCl isfiltered off. After evaporation of the solvents, 4.25 g of the expectedproduct are obtained.

PREPARATION 2.4

3-Cyclopropyl-4-hydrazinobenzoic acid hydrochloride.

A) 4-Acetamido-3-cyclopropylbenzonitrile.

1.67 g of CuCN are added to a solution of 4.3 g of4-bromo-2-cyclopropylacetanilide (prepared according to J. Am. Chem.Soc., 1968, 90 3404) in 100 ml of DMF, and the mixture is heated toreflux for 24 hours. It is poured into 30 ml of water, the resultingmixture is filtered, and the precipitate is washed with water and thenstirred for 30 minutes in a mixture of 59 ml of water and 25 ml ofethylenediamine. After extraction with 100 ml of AcOEt, drying over Na₂SO₄ and evaporation under vacuum, 2.39 g of the expected product areobtained.

NMR: 0.6:u.c.:2H; 0.9:u.c.:2H; 1.9: u.c.:1H; 2.1:s:3H; 7.3:d:1H;7.5:dd:1H; 7.8:d:1H; 9.5:bs:1H.

B) 4-Amino-3-cyclopropylbenzonitrile hydrochloride.

A mixture of 2.39 g of the product of step A dissolved in 45 ml ofethanol with 36 ml of water and 5 ml of concentrated HCl is stirred for12 hours under reflux. The ethanol is evaporated off under vacuum, andthe precipitate is filtered off, washed with 1 ml of water and driedunder vacuum to obtain 1.5 g of the expected product.

NMR: 0.5:u.c.:2H; 0.9:u.c.:2H; 1.6: u.c.:1H; 6.7:d:1H; 7.1-7.3:mt:2H;8:bs:2H.

C) 4-Amino-3-cyclopropylbenzoic acid hydrochloride.

1.3 g of the product of step B in 21 ml of 50% KOH are stirred for 29hours under reflux. After acidification to pH 1 with concentrated HCl,the mixture is filtered and the residue is dried under vacuum to obtain0.96 g of the expected product.

NMR: 0.5:u.c.:2H; 0.9:u.c.:2H; 1.7:u.c.:1H; 5.9:bs:2H; 6.6:d:1H;7.4:s:1H; 7.5:mt:1H; 12:bs:1H.

D) 3-cyclopropyl-4-hydrazinobenzoic acid hydrochloride.

A solution of 0.38 g of NaNO₂ in 4.5 ml of water is added slowly to asolution, cooled to -5° C., of 0.95 g of the product obtained in step Cin 22 ml of concentrated HCl and 21 ml of AcOH, and the mixture isstirred for 1 h 15 min at 0° C. It is cooled to -10° C., and a solutionof 3.76 g of SnCl₂ ·2H₂ O in 8 ml of concentrated HCl is added slowly.After 4 hours of stirring at RT, the mixture is filtered, and theresidue is washed with 2 ml of concentrated HCl and dried under vacuumto obtain 1 g of expected product.

NMR: 0.6:u.c.:2H; 1:u.c.:2H; 1.9: u.c.:1H; 7.1:d:1H; 7.6:s:1H; 7.8:d:1H;8.4:s:1H; 10.7:bs:

PREPARATION 2.10

5-Hydrazino-2-chlorobenzoic acid hydrochloride.

A solution of 2.11 g of NaNO₂ in 40 ml of water is added over 30 minutesto a suspension, cooled to -2° C., of 5 g of 5-amino-2-chlorobenzoicacid in 50 ml of concentrated HCl. The solution is stirred for 2 hoursat -3° C. and cooled to -10° C., and a solution of 23 g of SnCl₂ ·2H₂ Oin 20 ml of concentrated HCl and 20 ml of water is added over 30minutes. The mixture is stirred for one and a half hours at 0° C. andfiltered, and the precipitate is dried to obtain 4 g of expectedproduct.

NMR: 7.6:bs:2H; 7.7:bs:1H; 8.4:bs: 1H; 11.0:bs:3H.

PREPARATION 2.11

3-Hydrazino-4-methylbenzoic acid hydrochloride.

A solution of 2.74 g of NaNO₂ in 28 ml of water is added over 30 minutesto a solution, cooled to -5° C., of 5 g of 3-amino-4-methylbenzoic acidin 120 ml of concentrated HCl and 40 ml AcOH, and the mixture is leftstirring for 1 hour 20 minutes at 0° C. After cooling to -10° C., asolution of 27.6 g of SnCl₂ ·2H₂ O in 28 ml of concentrated HCl is addedslowly. After stirring for 1 hour at RT, filtration, washing of theprecipitate with 5 ml of 1N HCl and drying over P₂ O₅ under vacuum, 6.15g of the expected product are obtained.

By working according to the above procedures, starting from correctlysubstituted aniline derivatives, the hydrazines described in Table 1below are prepared.

                  TABLE 1                                                         ______________________________________                                         ##STR59##                                                                                                       M.p. or NMR                                Preparation                                                                            R.sub.1 or R'.sub.1                                                                     R.sub.2  R.sub.3                                                                              (Salt)                                     ______________________________________                                        2.12                                                                          4-SO.sub.3 H       2-CH.sub.3                                                                             3-CH.sub.3                                                                           NMR                                                                           (H.sub.2 SO.sub.4)                         2.13     5-CO.sub.2 H                                                                            2-Cl     H      NMR                                                                           (HCl)                                      2.14     3-CO.sub.2 H                                                                            4-F      H      NMR                                        2.15     4-CN      2-CF.sub.3                                                                             H      125                                        2.16     4-CO.sub.2 H                                                                            2-CF.sub.3                                                                             H      170(dec.)                                                                     (HCl)                                      2.17     5-CO.sub.2 H                                                                            2-OCH.sub.3                                                                            H      NMR                                                                           (HCl)                                      ______________________________________                                    

NMR:

Preparation 2.12:2:s:3H; 2.4:s:3H; 6.5:d:1H; 7.5:d:1H; 9.9:bs:3H.

Preparation 2.13:7.6:bs:2H; 7.7:bs: 1H; 8.4:bs:1H; 11.0:bs:3H.

Preparation 2.14:7.3:u.c.:2H; 7.4:u.c. 1H; 8.4:bs:1H; 10.8:bs:3H.

Preparation 2.17:3.8:s:3H; 4.4:bs:1H; 7.0:d:1H; 3.6:d:1H; 10.0:bs:3H.

PREPARATION 2.18

N-(4-Hydrazino-3-isopropylphenyl)-4-methyl-benzenesulphonamide oxalate.

A) N-(2-Bromo-5-isopropyl-4-nitrophenyl)-4-methylbenzenesulphonamide.

A solution of 23.47 g of N-(4-nitrophenyl)-4-methylbenzenesulphonamidein 230 ml of THF is cooled to -30° C., 100 ml of a 2M solution ofisopropylmagnesium chloride in ether is added and the mixture is leftstirring for 30 minutes at -30° C. 10.3 ml of bromine are then added at-30° C., the mixture is left stirring for 15 minutes at this temperatureand the temperature is then allowed to rise to 20° C. 55 ml oftriethylamine are then added and the mixture is left stirring for 1 hourat RT. Water is added, the mixture is acidified to pH 3-4 by adding 10%HCl solution, the organic phase is separated after settling has takenplace, the aqueous phase is extracted with ether and the combinedorganic phases are dried over Na₂ SO₄. The organic phase is stirred inthe presence of animal charcoal, filtered and concentrated under vacuum.The residue is taken up in EtOH and the crystallized product formed isdrained. 11.6 g of the expected product are obtained, m.p.=132° C.

NMR: 1.0:d:6H; 2.32:s:3H; 3.12:s: 1H; 7.14:s:1H; 7.36:d:2H; 7.65:d:2H;8.08: s:1H; 10.25:bs:1H.

B) N-(4-Amino-3-isopropylphenyl)-4-methyl-benzenesulphonamide.

A mixture of 11.5 g of the compound obtained in the preceding step and 1g of palladium on charcoal (5% Pd) in 200 ml of MeOH and 30 ml of DMF ishydrogenated for 7 hours at RT and at a pressure of 1 bar. The catalystis filtered off and the filtrate is concentrated under vacuum. Theresidue is taken up with water, the mixture is neutralized to pH 7 byadding 10% NaOH solution and extracted with AcOEt, the organic phase isdried over Na₂ SO₄ and the solvent is evaporated off under vacuum. 8 gof the expected product are obtained.

NMR: 1.01:d:6H; 2.4:s:3H; 2.89:mt: 1H; 4.91:bs:2H; 6.42-6.68:u.c.:3H;7.35:d: 2H; 7.56:d:2H; 9.38:s:1H.

C) N-(4-Hydrazino-3-isopropylphenyl)-4-methyl-benzenesulphonamideoxalate.

A mixture of 6.68 g of the compound obtained in the preceding step and70 ml of concentrated HCl solution is stirred at 0° C., a solution of1.48 g of NaNO₂ in 5 ml of water is added and the resulting mixture isleft stirring for 1 hour at 0° C. A solution of 11.35 g of sodiumdithionite in 60 ml of water is then added and stirring is continued for1 hour at 0° C. 120 g of powdered sodium acetate and 300 ml of water arethen added and the reaction mixture is left stirring for 30 minutes at0° C. It is extracted with AcOEt, the organic phase is dried over Na₂SO₄ and filtered, a solution of 1.98 g of oxalic acid in a minimumamount of EtOH is added to the filtrate and the mixture is concentratedunder vacuum. The residue is taken up in isopropyl ether, the mixture isleft stirring for 12 hours and the precipitate formed is drained. 4.84 gof the expected product are obtained, which product is used withoutfurther treatment.

PREPARATION 2.19

1-Hydrazino-2-methyl-4-nitrobenzene hydrofluoride.

A mixture of 4.6 g of 1-fluoro-2-methyl-4-nitrobenzene and 3 ml ofhydrazine hydrate in 45 ml of 2-propanol is heated to reflux for 2hours. 3 ml of hydrazine hydrate are added, refluxing is continued for 2hours and the mixture is left overnight with stirring at RT. Theprecipitate formed is drained. 3.53 g of the expected product areobtained, m.p.=182° C.

PREPARATION 2.20

N-(4-Hydrazino-3-isobutylphenyl)-4-methylbenzenesulphonamidehydrobromide.

A) N-(2-Bromo-5-isobutyl-4-nitrophenyl)-4-methylbenzenesulphonamide.

This compound is prepared according to the procedure described in step Aof Preparation 2.18, from 10 g ofN-(4-nitrophenyl)-4-methylbenzenesulphonamide in 100 ml of THF and 42.6ml of a 2M solution of isobutylmagnesium chloride in ether, followed by4.4 ml of bromine and 23.4 ml of triethylamine. 5.9 g of the expectedproduct are obtained, m.p.=170° C.

NMR: 0.8:d:6H; 1.7:mt:1H; 2.35:s: 3H; 2.6:d:2H; 7.2:s:1H; 7.3:d:2H;7.4:d: 2H; 8.2:s:1H; 10.25:s:1H.

B) N-(4-Amino-3-isobutylphenyl)-4-methylbenzenesulphonamide.

This compound is prepared according to the procedure described in step Bof Preparation 2.18, from 4.7 g of the compound obtained in thepreceding step. 2.8 g of the expected product are obtained.

NMR: 0.8:d:6H; 1.75:mt:1H; 2.2:d: 2H; 2.4:s:3H; 4.8:s:2H; 6.45:d:1H;6.5:d 1H; 6.65:dd:1H; 7.35:d:2H; 7.55:d:2H; 9.4:s:1H.

C) N-(4-Hydrazino-3-isobutylphenyl)-4-methyl-benzenesulphonamidehydrobromide.

This compound is prepared according to the procedure described in step Cof Preparation 2.18, from 2.5 g of the compound obtained in thepreceding step, 35 ml of concentrated HCl, 50 ml of acetic acid and 0.53g of NaNO₂, followed by 4.78 g of sodium dithionite in 50 ml of water,140 g of sodium acetate and 70 ml of water. After 30 minutes of stirringat 0° C., hydrobromic acid is added at 0° C. and the crystallizedproduct is drained and dried. 1.9 g of the expected product areobtained.

NMR: 0.65:d:6H; 1.6:mt:1H; 2.05:d: 2H; 2.2:s:3H; 6.05:bs:1H; 6.4:bs:1H;6.6-6.8:u.c.:2H; 7.2:d:2H; 7.4:d:2H.

PREPARATION 2.21

N-(4-Hydrazino-3-cyclopentylphenyl)-4-methyl-benzenesulphonamideoxalate.

A) N-(2-Bromo-5-cyclopentyl-4-nitrophenyl)-4-methylbenzenesulphonamide.

This compound is prepared according to the procedure described in step Aof Preparation 2.18, from 15 g ofN-(4-nitrophenyl)-4-methylbenzenesulphonamide in 100 ml of THF and 64 mlof a 2M solution of cyclopentylmagnesium chloride in ether, followed by6.8 ml of bromine and 35 ml of triethylamine. 6.1 g of the expectedproduct are obtained, m.p.=122° C.

NMR (DMSO+TFA): 1.25:mt:2H; 1.5-1.7: u.c.:4H; 1.95:mt:2H; 2.36:s:3H;3.2:qt: 1M; 7.12:s:2H; 7.4:d:2H; 7.7:d:2H; 8.08:s:1H.

B) N-(4-Amino-3-cyclopentylphenyl)-4-methyl-benzenesulphonamide.

This compound is prepared according to the procedure described in step Bof Preparation 2.18, from 6 g of the compound obtained in the precedingstep. 4.25 g of the expected product are obtained, m.p.=128° C.

NMR (DMSO+TFA): 1.25:mt:2H; 1.5-1.75: u.c.:4H; 1.95:mt:2H; 2.3:s:3H;3.0:qt:1H; 7.0:dd:1H; 7.12:d:1H; 7.2:d:1H; 7.34:d: 2H; 7.65:d:2H.

C) N-(4-Hydrazino-3-cyclopentylphenyl)-4-methyl-benzenesulphonamideoxalate.

This compound is prepared according to the procedure described in step Cof Preparation 2.18, from 3.35 g of the compound obtained in thepreceding step, 20 ml of H₂ SO₄, 50 ml of acetic acid, 10 ml of waterand 0.69 g of NaNO₂, followed by 5.5 g of sodium dithionite in 50 ml ofwater and 200 g of sodium acetate and 300 ml of water. 2.42 g of theexpected product are obtained.

PREPARATION 2.22

4-Hydrazino-2-isopropylbenzoic acid hydrochloride.

A) 4-Iodo-3-isopropylacetanilide.

This compound is prepared according to the process described in Bull.Soc. Chim. Jap., 1989, 62, 1349.

5.7 g of zinc chloride and 10.8 g of benzyltrimethylammoniumdichloroiodate are added at RT to a solution of 5 g of3-isopropylacetanilide in 150 ml of acetic acid, and the mixture is leftstirring for 2 days. It is concentrated under vacuum, the residue istaken up with 100 ml of a 5% solution of sodium hydrogen sulphite, themixture is brought to pH 5-6 by adding 10% Na₂ CO₃ solution andextracted 4 times with 200 ml of chloroform and the organic phase isdried over Na₂ SO₄. After filtration, the filtrate is chromatographed on100 g of alumina, eluting with chloroform. 5.2 g of the expected productare obtained.

NMR: 1.1:d:6H; 2.0:s:3H; 3.06:u.c.: 1H; 7.28:dd:1H; 7.5:d:1H; 7.72:d:1H;10.0: bs:1H.

B) 4-Iodo-3-isopropylaniline.

A mixture of 5.1 g of the compound obtained in the preceding step in 40ml of 96% EtOH and 25 ml of concentrated NaOH is heated to reflux for 6hours. It is concentrated under vacuum and extracted with ether, theorganic phase is dried over Na₂ SO₄ and the solvent is evaporated offunder vacuum. 5 g of the expected product are obtained in the form of anoil.

NMR: 1.16:d:6H; 2.94:u.c.:1H; 5.2:bs:2H; 6.2:dd:1H; 6.6:d:1H; 7.4:d:1H.

C) 4-Amino-2-isopropylbenzoic acid.

40 ml of water and 11 g of K₂ CO₃ are added to a solution of 5 g of thecompound obtained in the preceding step in 60 ml of DMF, and thesolution is then degassed for 10 minutes by bubbling nitrogen throughit. 0.5 g of palladium(II) acetate are then added and the reactionmixture is thereafter degassed for 10 minutes by bubbling nitrogenthrough it. It is placed under a pressure of 1 bar of carbon monoxidefor 10 hours and with stirring. The solution is filtered, the filter iswashed 4 times with 20 ml of water and the filtrate is concentratedunder vacuum. The residue is taken up with 50 ml of water and 10 ml ofsaturated NaCl solution, the aqueous phase is washed with ether andacidified to pH 3.5-4 by adding concentrated HCl and extracted withAcOEt, the organic phase is washed with saturated NaCl solution anddried over Na₂ SO₄ and the solvent is evaporated off under vacuum. 2 gof a crude product are obtained, which product is taken up in 20 ml of asaturated solution of HCl gas in methanol, and the mixture is heated toreflux overnight. It is concentrated under vacuum, the residue is takenup in 20 ml of water, and the mixture is alkalinized to pH 8 by addingconcentrated NaOH and extracted with 30 ml of DCM. 0.8 ml of aceticanhydride, NaHCO₃ and Na₂ SO₄ are added to the organic phase, which isleft stirring. After filtration, the filtrate is concentrated undervacuum and the residue is chromatographed on silica, eluting with aDCM/ether (50:50; v/v) mixture. 0.8 g of 4-acetamido-2-isopropylbenzoicacid methyl ester is obtained in the form of an oil. A mixture of 0.8 gof the product obtained and 3 g of KOH in 10 ml of water and 2 ml of1,2-dimethoxyethane is heated to reflux overnight. After cooling to RT,the reaction mixture is washed with ether, the aqueous phase isacidified to pH 3-4 by adding concentrated HCl and extracted with AcOEt,the organic phase is dried over Na₂ SO₄ and the solvent is evaporatedoff under vacuum. 0.6 g of the expected product is obtained.

NMR: 1.17:d:6H; 4.0:sp:1H; 5.7:bs:2H; 6.36:dd:1H; 6.80:d:1H; 7.6:d:1H;11.80:BS:1H.

D) 4-Hydrazino-2-isopropylbenzoic acid hydrochloride.

A mixture of 0.5 g of the compound obtained in the preceding step in 7ml of concentrated HCl is cooled to 0° C., a solution of 0.23 g of NaNO₂in 4 ml of water is added and the resulting mixture is left stirring for1 hour 30 minutes at 0° C. It is cooled to -10° C. and a solution of 2.6g of SnCl₂. 2H₂ O in 5 ml of concentrated HCl and 3 ml of water isadded, and the resulting mixture is left stirring for 2 hours at 0° C.The precipitate formed is drained, washed with concentrated HCl anddried at 50° C. under vacuum. 0.36 g of the expected product isobtained.

NMR: 1.15:d:6H; 3.98:u.c.:1H; 6.7:dd 1H; 6.96:d:1H; 7.8:d:1H; 8.2:bs:1H;13: bs:4H.

PREPARATION 2.23

1-Hydrazino-4-nitro-5,6,7,8-tetrahydronaphthalene hydrochloride.

A) 1-Acetamido-5,6,7,8-tetrahydronaphthalene.

A mixture of 24.39 g of 1-amino-5,6,7,8-tetrahydronaphthalene and 18.6ml of acetic anhydride in 230 ml of DCM is left stirring for 1 hour atRT. It is concentrated under vacuum, the residue is taken up with etherand the precipitate formed is drained. 26.8 g of the expected productare obtained, m.p.=158° C.

B) 1-Amino-4-nitro-5,6,7,8-tetrahydronaphthalene.

A mixture of 13 g of the compound obtained in the preceding step in 72ml of concentrated sulphuric acid is cooled to 0° C., a mixture of 4.55ml of nitric acid (d=1.4) and 22 ml of concentrated sulphuric acid isadded and the resulting mixture is left stirring for 45 minutes at 0° C.The reaction mixture is poured onto ice and the precipitate formed isdrained. The precipitate is taken up in 145 ml of EtOH, 30 ml ofconcentrated HCl and 30 ml of water and the mixture is heated to refluxfor 1 hour 30 minutes. 70 ml of the reaction mixture are evaporated, 220ml of water are added to the remaining solution, the pH is brought to 7by adding concentrated ammonium hydroxide solution and the precipitateformed is drained and dried. The precipitate is taken up with 210 ml ofnitrobenzene, the mixture is cooled 0° C. and a stream of HCl gas isbubbled through it for 50 minutes. The precipitate formed is drained andwashed with ether. The precipitate is taken up with MeOH, the mixture isneutralized by adding concentrated ammonium hydroxide solution, water isadded and the precipitate is drained. 5.15 g of the expected product areobtained after drying, m.p.=114° C.

C) 1-Hydrazino-4-nitro-5,6,7,8-tetrahydronaphthalene hydrochloride.

A mixture of 3.8 g of the compound obtained in the preceding step in 70ml of concentrated HCl is cooled to 3° C., a solution of 1.34 g of NaNO₂in 2 ml of water is added and the resulting mixture is left stirring for2 hours at 3° C. A solution of 18.2 g of SnCl₂ ·2H₂ O in 90 ml ofconcentrated HCl is then added, the mixture is left stirring for 30minutes at 3° C. and the temperature is then allowed to rise to RT. Theprecipitate formed is drained and dried. 6.3 g of the expected productare obtained, mixed with tin salts.

NMR (DMSO+TFA): 1.7:mt:4H; 2.55:mt:2H; 2.85:mt:2H; 6.88:d:1H; 7.85:d:1H.

PREPARATION 2.24

3-Diethylamino-N-(4-isopropyl-3-hydrazinophenyl)-propionamide.

A) 3-Diethylamino-N-(4-isopropyl-3-nitrophenyl)-propionamide oxalate.

4 g of 4-isopropyl-3-nitroaniline (prepared according to J. Org. Chem.,1954, 19, 1067) are treated by heating to reflux for 1 hour with 8.14 mlof bis-(trimethylsilyl)acetamide in 20 ml of acetonitrile, and the acidchloride prepared from 4 g of 3-(N,N-diethylamino)propanoic acidhydrochloride in DCM is added, followed by 8.9 ml of triethylamine.After 1 hour of stirring at RT, the mixture is evaporated to dryness,the residue is extracted with DCM, and the mixture is washed with waterand then with 5% NaOH. After drying over Na₂ SO₄, the mixture isevaporated under vacuum, the oil obtained is redissolved in the minimumMount of ethanol, and 1.2 g of oxalic acid are added. After 2 hours ofstirring, the mixture is filtered to obtain 4.5 g of the expectedoxalate, m.p.=165° C.

B) 3-Diethylamino-N-(4-isopropyl-3-aminophenyl)-propionamide oxalate.

A solution of 4.5 g of nitro derivative obtained in the preceding stepin 100 ml of MeOH and 10 ml of DMF is hydrogenated for 5 hours withRaney® nickel. After the catalyst has been filtered off, the mixture isconcentrated under vacuum, precipitation is induced by adding isopropylether and the mixture is left stirring for 1 hour at RT. Afterfiltration, 3 g of the expected aniline oxalate are obtained, m.p.=127°C.

C) 3-Diethylamino-N-(4-isopropyl-3-hydrazinophenyl)propionamide.

0.67 g of NaNO₂ dissolved in the minimum amount of water is added to amixture, cooled to 0° C, of 2.7 g of amine obtained in the precedingstep and 30 ml of concentrated HCl, and the resulting mixture is leftstirring for 1 hour at 0° C. 5 g of sodium dithionite dissolved in theminimum amount of water are then added and the mixture is stirred for afurther 30 minutes at 0° C. 50 g of powdered sodium acetate are addedand the mixture is stirred for 30 minutes at 0° C. 50 g of water areadded and a few impurities are extracted with AcOEt. The aqueous phaseis saturated with NaCl, the pH is raised to 9 with 20% NH₄ OH andextracted with DCM, and the organic phase is dried over Na₂ SO₄ andevaporated under vacuum. The residue is allowed to crystallize inpentane overnight and is filtered off to obtain 3.26 g of expectedhydrazine, m.p.=77°-80° C.

PREPARATIONS OF THE ESTERS IIa, II'a PREPARATION 3.1

1-(4-Carboxy-2-isopropylphenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a:R'₁ =4--CO₂ H; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

A mixture containing 0.96 g of the product obtained in Preparation 2.1and 1.2 g of compound A obtained in Preparation 1.1 in 15 ml of aceticacid is brought to reflux for 5 hours. After 3 days at RT, it is pouredinto a mixture of water and ice. The precipitate formed is filtered off,rinsed with water and then dried over P₂ O₅. 1.34 g of the expectedproduct are obtained, m.p.=228°-230° C.

NMR: 0.85:d:6H; 2.55:sp:1H; 3.5:s:6H; 3.75:s:3H; 6.5:d:2H; 6.75:s:1H;7.05-7.3:u.c.:2H; 7.7:d:1H; 13.05:bs:1H.

PREPARATION 3.1a

1-(4-Carboxy-2-isopropylphenyl)-5-(2.6-dimethoxy-phenyl)-3-pyrazolecarboxylicacid ethyl ester.

By reacting the product of Preparation 2.1 or 2.1a with compound A1according to the procedure of Preparation 3.1, and afterrecrystallization in AcOEt, the expected ethyl ester is obtained,m.p.=231° C.

PREPARATION 3.2

1- 4-N-Methyl-N-(3-(N',N'-dimethylamino)propyl)-carbamoyl!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =4--CON(CH₃)(CH₃)₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

A)1-(4-Chloroformyl-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid methyl ester.

A mixture is prepared containing 26 g of the product obtained inPreparation 3.1 and 170 ml of thionyl chloride. It is left stirring atRT for 1 day. It is evaporated under vacuum, the residue is taken upwith DCM, the mixture is evaporated and the operation is repeated 3times.

B) 1- 4-N-Methyl-N-(3-(N',N'-dimethylamino)-propyl)carbamoyl!-2-isopropylphenyl!-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylicacid methyl ester.

9.3 ml of triethylamine and 9.9 ml ofN,N,N'-trimethyl-1,3-propanediamine are added to 50 ml of DCM. Theproduct obtained in the preceding step in 280 ml of DCM is added undernitrogen, and the mixture is left stirring at RT for three and a halfhours. After washing with water (twice), the mixture is dried over MgSO₄and evaporated under vacuum. The residue is taken up with ether. Afterthe insoluble matter has been filtered off, and evaporation, the residueis chromatographed on silica, eluting with DCM/MeOH/H₂ O (95:5:0.5;v/v/v, to 88:12:0.8; v/v/v). 24.5 g of the expected product areobtained.

NMR: 0.95:d:6H; 1.7:u.c.:2H; 1.9-2.4: u.c.:8H; 2.95:ss:3H; 3.5:u.c.:2H;3.7:s: 6H; 3.9:s:9H; 6.7:d:2H; 6.9:s:1H; 7.1-7.5: u.c.:4H.

PREPARATION 3.2a

1- 4-N-Methyl-N-(3-(N',N'-dimethylamino)propyl)-carbamoyl!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid ethyl ester.

A)1-(4-Chloroformyl-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid ethyl ester.

26 g of the product of Preparation 3.1 or 3.1a are added to 50 ml ofSOCl₂ cooled to 5°, and the mixture is stirred for 5 hours at RT whilenitrogen is bubbled through in the dry state. After evaporation undervacuum, the residue is taken up with DCM and evaporated under vacuum;the operation is repeated twice.

The acid chloride may also be prepared according to the procedure A'below:

A') 2.5 ml of SOCl₂ is added to a solution of 5 g of the product ofPreparation 3.1 or 3.1a in 50 ml of DCM, and the mixture is heated toreflux for 3 hours and evaporated under vacuum, the residue is taken upwith DCM and the mixture is evaporated under vacuum; the operation iscarried out twice.

B) 1- 4-N-Methyl-N-(3-(N',N'-dimethylamino)-propyl)carbamoyl!-2-isopropylphenyl!-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylicacid ethyl ester.

A solution of acid chloride obtained in step A in 220 ml of DCM is addedunder dry nitrogen to a solution of 9 ml of triethylamine and 9.5 ml ofN,N,N'-trimethyl-1,3-propanediamine in 50 ml of DCM, and the mixture isstirred overnight. It is washed twice with water and the aqueous phasesare extracted twice with DCM. The combined organic phases are dried overMgSO₄ and evaporated under vacuum. The residue is stirred with 300 ml ofether, some insoluble matter is filtered off, and the filtrate isdecolorized on animal charcoal and evaporated to obtain 28.8 g of theexpected product in the form of an oil.

NMR (DMSO+TFA): 1:d:6H; 1.3:t:3H; 1.8-2.1:u.c.:2H; 2.65:qt:1H;2.7-3.05:u.c.: 9H; 3.15:mt:2H; 3.5:mt:2H; 3.65:s:6H; 4 .35:qr:2H;6.6:d:2H; 6.85:s:1H; 7.2-7.4:u.c.:4H.

The product of step B may also be obtained according to the proceduredescribed below:

B') A solution of the acid chloride obtained in step A' in 37.5 ml ofDCM is added to a solution of 1.32 g ofN,N,N'-trimethyl-1,3-propanediamine in 37.5 ml of 3N sodium hydroxide.After 1 hour of stirring, 25 ml of chloroform and 25 ml of water areadded, settling is allowed to take place, and the organic phase isseparated, dried over Na₂ SO₄ and evaporated under vacuum to obtain 6.1g of the expected product.

PREPARATION 3.3

1- 4-N-(2-Cyanoethyl)carbamoyl!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =4--CONHCH₂ CH₂ CN; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

0.935 g of 3-aminopropionitrile hemifumarate is mixed with 3.7 ml of1.3N NaOH, the mixture is extracted with DCM, the organic phase is driedover Na₂ SO₄ and the solvent is evaporated off under vacuum. The residueis taken up in 6 ml of DCM, 0.96 ml of triethylamine is added, and asolution of 2.45 g of the compound obtained in step A of Preparation 3.2in 30 ml of DCM is then added slowly. The mixture is left stirringovernight at RT and under a nitrogen atmosphere. Some insoluble matteris filtered off, the filtrate is washed with water, with saturatedNaHCO₃ solution and with water and dried over Na₂ SO₄, and the solventis evaporated off under vacuum. 2.24 g of the expected product areobtained, m.p.=114°-116° C. (dec.).

NMR: 1:d:6H; 2.7:mt:1H; 2.8:t:2H; 3.5:q:2H; 3.65:s:6H; 3.9:s:3H; 6.7:d:2H; 6.9:s:1H; 7.3-7.4:u.c.:2H; 7.75:d:1H; 7.9:s:1H; 9:t:1H.

By reacting the appropriate primary amine with the compound obtained inPreparation 3.2, step A, and working according to the proceduredescribed for Preparation 3.2, step B, the esters described in Table 2below are prepared.

                  TABLE 2                                                         ______________________________________                                         ##STR60##                                                                    Preparation                                                                           R.sub.1              M.p °C. or NMR                            ______________________________________                                        3.4     CONH(CH.sub.2).sub.3 NMe.sub.2                                                                     NMR                                              3.5     CONH(CH.sub.2).sub.2 NMe.sub.2                                                                     NMR                                              3.6     CONH(CH.sub.2).sub.3 NEt.sub.2                                                                     NMR                                              (IIa. HCl)                                                                    3.7                                                                                    ##STR61##           NMR                                              3.8                                                                                    ##STR62##           NMR                                              3.9                                                                                    ##STR63##           NMR                                              3.10                                                                                   ##STR64##           NMR                                              3.11                                                                                   ##STR65##           NMR                                              ______________________________________                                    

NMR:

Preparation 3.4:1:d:6H; 1.65:mt:2H; 2.1:s:6H; 2.25:t:2H; 2.6:mt:1H;3.25:u.c.:2H; 3.6:s:6H; 3.85:s:3H; 6.6:d:2H; 6.85:s:1H; 7.2-7.3:u.c.:2H;7.6:dd:1H; 7.8:d: 1H; 8.6:t:1H.

Preparation 3.5:(DMSO+TFA) 1:d:6H; 2.6mt:2H; 2.8:s:6H; 3.25:mt:2H;3.6:u.c.+s: 8H; 3.85:s:3H; 6.6:d:2H; 6.8:s:1H; 7.2-7.4:u.c.:2H;7.7:d:1H; 7.8:d:1H.

Preparation 3.6:(DMSO+TFA): 0.9:d:6H; 1.15:t:6H; 1.8-2:u.c.:2H;2.6:mt:1H; 3.1: mt:4H; 3.3:t:2H; 3.55:u.c.+s:8H; 3.8:s: 3H; 6.5:d:2H;6.8:s:1H; 7.15-7.3:u.c.:2H; 7.6:dd:1H; 7.8:bs:1H.

Preparation 3.7:1.05:d:6H; 1.7:mt:4H; 2.45-2.75:u.c.:7H; 3.4:mt:2H;3.7:s:6H; 3.9:S:3H; 6.65:d:2H; 6.9:s:1H; 7.3-7.4:u.c.: 2H;7.7-7.9:u.c.:2H; 8.6:t:1H.

Preparation 3.8:1.05:d:6H; 2.7:mt:1H; 3.7:s:6H; 3.9:s:3H; 6.7:d:2H;6.9:s:1H; 7.2-7.4:u.c.:3H; 7.85-8.5:u.c.:5H; 11:s:1H.

Preparation 3.9:0.9:s:6H; 1.05:d:6H; 2.25:s:2H; 2.3:s:6H; 2.7:mt:1H;3.2:d: 2H; 3.7:s:6H; 3.9:s:3H; 6.65:d:2H; 6.9:bs 1H; 7.3-7.4:u.c.:2H;7.6-7.8:u.c.:2H; 8.7:t:1H.

Preparation 3.10:1:d:6H; 1.4-1.9:u.c.: 4H; 2:t:2H; 2.6:mt:1H; 2.8:d:2H;3.5:s: 2H; 3.6:s:6H; 3.6-3.85:u.c.:1H; 3.85:s:3H; 6.6:d:2H; 6.85:s:1H;7.1-7.4:u.c.:5H; 7.65 d:1H; 7.8:s:1H; 8.3:d:1H.

Preparation 3.11 (DMSO+TFA): 1.05:d:6H; 1.6-2.3:u.c.:5H; 2.7:mt:1H;3.2-3.4:u.c.: 5H; 3.5-3.8:u.c.+s:7H; 3.9:s:3H; 4.3-4.4:u.c.: 1H;6.65:d:2H; 6.9:s:1H; 7.3-7.4:mt:2H; 7.8:d:1H; 7.9:s:1H.

PREPARATION 3.12

5-(2,6-Dimethoxyphenyl)-1-(2-isopropyl-4-sulphophenyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a:R'₁ =4-SO₃ H; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

A mixture containing 0.82 g of 3-isopropyl-4-hydrazinobenzenesulphonicacid obtained in Preparation 2.2 and 1.26 g of compound A obtained inPreparation 1.1 in 15 ml of acetic acid is heated to reflux for 5 hours.After evaporation, the residue is dissolved in DCM, and the solution iswashed with normal HCl and decolorized on activated charcoal. It isdried and evaporated, the residue is then stirred under reflux inisopropyl ether and the mixture is filtered while hot. 1.28 g of theexpected product are obtained.

NMR: 1:d:6H; 2.6:mt:1H; 3.6:s:6H; 3.8:s:3H; 6.6:d:2H; 6.8:s:1H; 7.15:d:1H; 7.3:t:1H; 7.4:d:1H; 7.5:s:1H.

PREPARATION 3.13

5-(2,6-Dimethoxyphenyl-1-2-isopropyl-4-(N-methyl-N-(3-(N',N'-dimethylamino)propyl)aminosulphonyl)-phenyl!-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =-4-SO₂ NMe(CH₂)₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

A)5-(2,6-Dimethoxyphenyl)-1-(4-chlorosulphonyl-2-isopropylphenyl)-3-pyrazolecarboxylicacid methyl ester.

1.08 g of the product obtained in Preparation 3.12 and 4 ml of POCl₃ areleft stirring at RT for 24 hours, and stirring is then continued at 70°C. for a further 24 hours. The reaction medium is evaporated twice withtoluene and 1.6 g of the expected product are obtained.

B) 5-(2,6-Dimethoxyphenyl)-1-2-isopropyl-4-(N-methyl-N-(3-(N',N'-dimethylamino)propyl)aminosulphonyl)-phenyl!-3-pyrazolecarboxylicacid methyl ester.

1.8 ml of N,N,N'-trimethyl-1,3-propanediamine and then 2 ml oftriethylamine are added to a suspension of 1.6 g of the product obtainedin the preceding step in 10 ml of toluene and 5 ml of DCM. The mixtureis left stirring for 3 hours at RT and then one and a half hours at 50°C. After filtration and evaporation to dryness, the residue is extractedwith ether and then with AcOEt. The organic phase is washed with water,dried over Na₂ SO₄ and evaporated under vacuum. 1.13 g of the expectedproduct are obtained.

NMR: 0.85:d:6H; 1.45:mt:2H; 2:s: 6H; 2.6:s+mt:4H; 2.85:t:2H; 3.5:s:6H;3.8: s:3H; 6.5:d:2H; 6.8:s:1H; 7.2:t:1H; 7.4: d:1H; 7.5-7.6:u.c.:2H.

PREPARATION 3.14

5-(2,6-Dimethoxyphenyl)-1-(4-carboxy-5,6,7,8-tetrahydro-1-naphthyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a:R'₁ =4-CO₂ H; R₂, R₃ =--(CH₂)₄ --; R₄ =CH₃).

A mixture of 0.67 g of hydrazine obtained in Preparation 2.3 and 0.83 gof compound A in 6 ml of AcOH is stirred under reflux for 2 hours. It isextracted with DCM, and the organic phase is washed with water, driedover MgSO₄ and evaporated under vacuum. The residue is chromatographedon silica, eluting with a DCM/MeOH (100:2; v/v) mixture to obtain 0.7 gof expected product.

NMR: 1.4-2:u.c.:4H; 2.3-3.1:u.c.:4H; 3.4-4:u.c. 9H; 6.6:d:2H;6.8-7.6:u.c.:4H; 12.95:bs:1H.

PREPARATION 3.15

5-(2,6-Dimethoxyphenyl)-1-{4-N-(3-(N',N'-dimethylamino)propyl)carbamoyl!-5,6,7,8-tetrahydro-1-naphthyl}-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =4-CONH(CH₂)₃ NMe₂ ; R₂, R₃ =--(CH₂)₄ --; R₄ =CH₃).

A solution of 0.7 g of product obtained in Preparation 3.14 in 6 ml ofSOCl₂ and 30 ml of DCM is heated for one and a half hours at 40° C. Itis evaporated under vacuum, the acid chloride is then redissolved in 5ml of DCM, the mixture is cooled to 5° C. and 0.225 ml ofN,N-dimethylpropylenediamine and 0.225 ml of triethylamine are added.After stirring for 2 hours at RT, the mixture is evaporated undervacuum, the residue is redissolved in DCM, and the mixture is washedwith water, dried over MgSO₄ and evaporated under vacuum to obtain 0.79g of expected product.

PREPARATION 3.16

5-(2,6-Dimethoxyphenyl)-1-(4-sulpho-5,6,7,8-tetrahydro-1-naphthyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a:R'₁ =4-SO₃ H; R₂, R₃ =--(CH₂)₄ --; R₄ =CH₃).

A mixture of 0.5 g of hydrazine obtained in Preparation 2.4 and 0.62 gof compound A in 4 ml of AcOH is heated to reflux for four and a halfhours. It is evaporated under vacuum, the residue is redissolved in DCM,and the mixture is washed twice with 1N HCl, dried over MgSO₄ andevaporated to obtain 1 g of expected product.

NMR: 1.7:bs:4H; 2.5:u.c.:2H; 3.2: u.c.:2H; 3.7:s:6H; 3.95:s:3H;6.7:d:2H; 6.8-6.9:u.c.:2H; 7.35:t:1H; 7.55:d:1H.

PREPARATION 3.17

5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-dimethylamino)ethyl)aminosulphonyl!-5,6,7,8-tetrahydro-1-naphthyl}-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =4-SO₂ NMe(CH₂)₂ NMe₂ ; R₂, R₃ =(CH₂)₄ ; R₄ =CH₃).

A mixture containing 1 g of acid obtained in Preparation 3.16 and 3 mlof POCl₃ is stirred for hours at RT and then three and a half hours at70° C. It is evaporated under vacuum, toluene is added and the mixtureis evaporated under vacuum (twice). The solution of the sulphonylchloride thereby obtained in 10 ml of DCM is added to a solution of 1.5ml of N,N,N'-trimethylethylenediamine and 1.5 ml of triethylamine in 10ml of DCM at 5° C. The mixture is left stirring for 4 days at 10° C.,filtered and evaporated under vacuum. After redissolution in DCM,washing with water and extraction of the aqueous phase with DCM, theorganic phase is dried over MgSO₄ and evaporated under vacuum to obtain1.07 g of expected sulphonamide, m.p.=90° C.

NMR: 1.6-1.8:u.c.:4H; 2.1:s:6H; 2.35: t:2H; 2.4-2.6:u.c. 2H; 2.9:s:3H;3.1:mt:2H; 3.2:t:2H; 3.6:s:6H; 3.9:s:3H; 6.7:d:2H; 6.9:s:1H; 7.1:d:1H;7.4:t:1H; 7.7:d:1H.

PREPARATION 3.18

5-(2,6-Dimethoxyphenyl)-1-(4-carbamoyl-2-methyl-phenyl)-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =4-CONH₂ ; R₂ =2-CH₃ ; R₃ =H; R₄ =CH₃).

A suspension of 0.39 g of the hydrazine obtained in Preparation 2.5 and450 mg of compound A in 5 ml of AcOH is heated to reflux for 8 hours.100 ml of water are added to the reaction medium; the precipitate formedis filtered off, then placed in 10 ml of isopropyl ether and heated toreflux for 30 minutes, and is filtered off. 300 mg of the expectedproduct are obtained, m.p.=219° C. On filtration of the aqueous phase 24hours later, a second crop of 70 mg of expected product are obtained inthe form of needles.

NMR: 2.05:s:3H; 3.5:s:6H; 3.8:s: 3H; 6.6:d:2H; 6.8:s:1H; 7:d:1H; 7.2:t:1H; 7.4:bs:1H; 7.6:d:1H; 7.7:s:1H; 7.9:bs 1H.

PREPARATION 3.19

5-(2,6-Dimethoxyphenyl)-1-(4-carboxy-2,3-di-methylphenyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a:R'₁ =4-CO₂ H; R₂ =2-CH₃ ; R₃ =3-CH₃ ; R₄ =CH₃).

A mixture of 4.5 g of the product of Preparation 2.6 and 12 g ofcompound A in 50 ml of AcOH is heated to reflux with stirring for 3hours. Precipitation is induced by pouring the mixture into 300 ml ofice-cold water, and the precipitate is filtered off and washed with 50ml of water. After stirring in 50 ml of ether, filtration and dryingunder vacuum over P₂ O₅, 5 g of expected product are obtained, m.p.=240°C.

PREPARATION 3.20

5-(2,6-Dimethoxyphenyl)-1-{2,3-dimethyl-4-N-(2-(N',N'-dimethylamino)ethyl)carbamoyl!phenyl}-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =4-CONH(CH₂)₂ NMe₂ ; R₂ =2-OCH₃ ; R₃ =3-CH₃ ; R₄ =CH₃).

After a solution of 2 g of the product of Preparation 3.19 in 10 ml ofSOCl₂ and 40 ml of DCM has been heated for one and a half hours at 40°C., it is evaporated under vacuum, the acid chloride is redissolved in10 ml of DCM and the mixture is poured into a solution of 0.54 ml ofN,N-dimethylaminoethylenediamine in 10 ml of DCM. 0.68 ml oftriethylamine is added and the mixture is stirred for 2 hours at RT.After evaporation under vacuum, extraction with 100 ml of DCM, washingwith water, drying over MgSO₄ and evaporation under vacuum, 1.8 g ofexpected product are obtained.

NMR: 1.9:s:3H; 2.2:s+s:9H; 2.4:t: 2H; 3.4:u.c.:2H; 3.6:s:6H; 3.8:s:3H;6.6: d:2H; 6.8:s:1H; 6.9-7.1:dd:2H; 7.3:t:1H; 8.2:t:1H.

PREPARATION 3.21

5-(2,6-Dimethoxyphenyl)-1-(4-carboxy-2-methoxy-phenyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a: R'₁ =4-CO₂ H; R₂ =2-0CH₃ ; R₃ =H; R₄ =CH₃).

A mixture of 4.8 g of the product of Preparation 2.7 and 5.6 g ofcompound A in 60 ml of AcOH is left stirring for 6 hours under reflux.After precipitation with 300 ml of ice-cold water, stirring for 30minutes, filtration, washing with water and then with pentane anddrying, 6 g of expected product are obtained, m.p.=210° C.

PREPARATION 3.22

5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carbamoyl!-2-methoxy-phenyl}-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =4-CONMe(CH₂)₂ NEt₂ ; R₂ =2-OCH₃ ; R₃ =H; R₄ =CH₃).

A solution of 2.5 g of the product of Preparation 3.21 in 30 ml of DCMand 5 ml of SOCl₂ is heated to reflux for three and a half hours. Afterevaporation under vacuum followed by 2 azeotropic evaporations with 20ml of DCM, the acid chloride formed is redissolved in 40 ml of DCM, andthe mixture is added to a solution of 1.1 ml ofN,N-diethyl-N'-methylethylenediamine and 1 ml of triethylamine in 40 mlof DCM and left stirring for 15 hours at RT. After evaporation undervacuum, the residue is chromatographed on silica, eluting with a solventgradient ranging from a DCM/MeOH (90:10; v/v) mixture to a DCM/MeOH/H₂ O(80:20:0.7; v/v/v) mixture to obtain 1.73 g of the expected product.

NMR: 0.7-1.1:mt:6H; 2.2-3.7:mt:20H; 3.85:s:3H; 6.55:d:2H; 6.8:s:1H;6.95:mt: 2H; 7.3:mt:2H.

PREPARATION 3.23

1-(4-Carboxy-2-chlorophenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylicacid ethyl ester.

(II'a:R'₁ =4-CO₂ H; R₂ =2-Cl; R₃ =H; R₄ =CH₃).

3-Chloro-4-hydrazinobenzoic acid is described in Patent U.S. 3,959,309.5.6 g of this acid and 8.75 g of compound A₁ in 100 ml of AcOH areheated to reflux for 6 hours. The reaction mixture is poured into 500 mlof ice-cold water, and the precipitate formed is filtered off and thenwashed with water, pentane and then isopropyl ether. The product isdried under vacuum to obtain 2 g of the expected compound.

PREPARATION 3.24

5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carbamoyl!-2-chlorophenyl}-3-pyrazolecarboxylicacid ethyl ester.

(IIa:R₁ =4-CONMe(CH₂)₂ NEt₂ ; R₂ =2-OCH₃ ; R₃ =H; R₄ =CH₃).

A solution of 2.5 g of the product of Preparation 3.23 in 30 ml of DCMand 4.5 ml of SOCl₂ is heated to reflux for 4 hours. After evaporationunder vacuum followed by 2 azeotropic evaporations with 20 ml of DCM,the acid chloride formed is redissolved in 40 ml of DCM, and the mixtureis then poured into a solution of 1.1 ml ofN,N-diethyl-N'-methylethylenediamine and 1 ml of triethylamine in 4 mlof toluene and left stirring for 15 hours at RT. After evaporation undervacuum, extraction of the residue with 100 ml of DCM, 2 washes withwater, drying over Na₂ SO₄ and evaporation under vacuum, the residue ischromatographed on silica H, eluting with a DCM/MeOH (90:10; v/v)mixture and then DCM/MeOH/H₂ O (90:10:0.5; v/v/v) to obtain 2.6 g ofexpected product.

NMR (DMSO+TFA): 2.8:s:3H; 3 to 3.7: u.c.:17H; 6.6:d:2H; 6.8:s:1H;7.05:u.c.: 2H; 7.3:u.c. 2H.

PREPARATION 3.25

5-(2,6-Dimethoxyphenyl)-1-4-(N-(2-morpholino-ethyl)carbamoyl)-2-chlorophenyl!-3-pyrazolecarboxylicacid ethyl ester. ##STR66##

A solution of 2.63 g of the product of Preparation 3.23 in 4.5 ml ofSOCl₂ and 30 ml of DCM is stirred under reflux for 4 hours. Afterevaporation under vacuum followed by 2 azeotropic evaporations with 30ml of toluene, the acid chloride formed is redissolved in 40 ml of DCM,and the mixture is added to a solution of 0.9 ml of4-(2-aminoethyl)morpholine and 1 ml of triethylamine in 4 ml of toluene.After stirring for 15 hours at RT, evaporation under vacuum,redissolution of the residue in 200 ml of DCM, washing with 100 ml ofsaturated NaCl solution, drying over Na₂ SO₄ and evaporation undervacuum, 3 g of expected product are obtained.

NMR: 1.3:t:3H; 2.3-2.6:mt:6H; 3.3:mt 2H; 3.5:mt:10H; 4.3:qr:2H;6.55:d:2H; 6.8 :s:1H; 7.1-7.4:mt:3H; 6.75:dd:1H; 6.9:dd: 1H; 8.6:t:1H.

PREPARATION 3.26

5-(2,6-Dimethoxyphenyl)-1-(3-chloro-4-cyano-phenyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a:R₁ =4-CN; R₂ =3-C₁ ; R₃ =H; R₄ =CH₃).

A mixture containing 4.2 g of the compound obtained in Preparation 2.8and 6 g of compound A in 10 ml of AcOH is heated on a water bath for 2hours. It is poured into ice-cold water, and the precipitate formed isfiltered off and then dried to obtain 3.78 g of the expected product.

PREPARATION 3.27

5-(2,6-Dimethoxyphenyl)-1-(4-carboxy-2-cyclo-propylphenyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a:R'₁ =4-CO₂ H; R₂ =2-cyclopropyl; R₃ =H; R₄ =CH₃).

A mixture of 1.28 g of compound A and 1 g of the product of Preparation2.9 in 12 ml of AcOH is stirred under reflux for 7 hours. Precipitationis induced with 120 ml of ice-cold water, and the precipitate isfiltered off, washed with water and dried under vacuum over P₂ O₅ toobtain 1.27 g of expected product.

NMR: 0.5:u.c.:2H; 0.8:u.c.:2H; 1.3:t 3H; 1.5:u.c.:1H; 3.6:s:6H;4.3:qr:2H; 6.6 d:2H; 6.9:s:1H; 7.3:u.c.:3H;77:bs:d:1H; 13:bs:1H.

PREPARATION 3.28

5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carbamoyl!-2-cyclopropyl-phenyl}-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =4-CON(Me)(CH₂)₂ NEt₂ ; R₂ =2-cyclo-propyl; R₃ =H; R₄ =CH₃).

A solution of 1.27 g of the product of Preparation 3.27 in 28 ml oftoluene and 2 ml of SOCl₂ is heated for 5 hours at 100° C. Afterevaporation under vacuum followed by 2 azeotropic evaporations with 30ml of toluene, the acid chloride obtained is redissolved in 19 ml ofDCM, and the mixture is poured slowly into a solution of 0.53 ml ofN,N-diethyl-N'-methylethylenediamine and 0.61 ml of triethylamine in 1.9ml of toluene. After stirring for 12 hours at RT, evaporation undervacuum, extraction with 100 ml of DCM, washing with water, drying overNa₂ SO₄ and evaporation under vacuum, 1.29 g of the expected product areobtained.

NMR: 0.4-1:u.c.:10H; 1.2:t:3H; 1.4: mt:1H; 2.1-3:u.c.:9H; 3.5:u.c.:8H;4.3:qr: 2H; 6.5:d:2H; 6.6:s:1H; 6.8:s:1H; 6.9-7.2: mt:3H.

PREPARATION 3.29

5-(2,6-Dimethoxyphenyl)-1-(3-carboxy-4-chloro-phenyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a:R'₁ =3-CO₂ H; R₂ =4-Cl; R₃ =H; R₄ =CH₃).

A mixture of 4 g of product of Preparation 2.10 and 4.6 g of compound Ain 60 ml of AcOH is heated to reflux with stirring for 5 hours. It ispoured into 100 ml of ice-cold water, and the precipitate is filteredoff and washed with 5 ml of water and then 20 ml of ether. It is driedunder vacuum to obtain 3 g of expected product, m.p.=206° C.

NMR: 3.55:s:6H; 3.85:s:3H; 6.7:d: 2H; 6.9:s:1H; 7.35:dd:1H; 7.4:t:1H;7.55: d:1H; 7.7:d:1H.

PREPARATION 3.30

5-(2,6-Dimethoxyphenyl)-1-{3-N-methyl-N-(2-(N',N'-dimethylamino)ethyl)carbamoyl!-4-chlorophenyl}-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =3-CON(Me)(CH₂)₂ NMe₂ ; R₂ =4-Cl; R₃ =H; R₄ =CH₃).

A solution of 1.5 g of the product of Preparation 3.29 in 20 ml of DCMand 2.6 ml of SOCl₂ is heated with stirring for three and a half hoursat 60° C. After evaporation under vacuum, the acid chloride isredissolved in 10 ml of DCM, and the mixture is poured into a solutionof 0.5 ml of N,N,N'-trimethylethylene-diamine and 0.6 ml oftriethylamine in 2.5 ml of toluene and then left stirring for 15 hoursat RT. After evaporation under vacuum, dissolution of the residue in 100ml of DCM, washing with 100 ml of water, drying over Na₂ SO₄ andevaporation under vacuum, 0.8 g of expected product is obtained.

PREPARATION 3.31

5-(2,6-Dimethoxyphenyl)-1-(5-carboxy-2-methyl-phenyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a:R'₁ =5-CO₂ H; R₂ =2-CH₃ ; R₃ =H; R₄ =CH₃).

A mixture of 6.15 g of the product of Preparation 2.11 and 7.76 g ofcompound A in 100 ml of AcOH is heated to reflux with stirring for oneand a half hours. After concentration under vacuum to 5 ml,precipitation with 20 ml of ice-cold water, filtration, washing of theprecipitate with 5 ml of water and drying over P₂ O₅ under vacuum at 80°C., 9.55 g of expected product are obtained, m.p.=189° C.

NMR: 1.20:t:3H; 3.55:s:6H; 4.26:qr: 2H; 6.58:d:2H; 6.80:s:1H; 7.20:t:1H;7.60: d:1H; 7.70:d:1H; 7.80:dd:1H.

PREPARATION 3.32

5-(2,6-Dimethoxyphenyl)-1-{5-N-methyl-N-(3-(N',N'-dimethylamino)propyl)carbamoyl!-2-methyl-phenyl}-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =5-CON(Me)(CH₂)₃ NMe₂ ; R₂ =2-CH₃ ; R₃ =H; R₄ =CH₃).

A solution of 2 g of the product of Preparation 3.31 in 10 ml of SOCl₂is left stirring for 5 hours at RT. After evaporation under vacuumfollowed by 3 azeotropic distillations with 30 ml of DCM, the acidchloride formed is redissolved in 25 ml of DCM, and the mixture ispoured into a solution of 0.81 ml of N,N,N'-trimethyl-1,3-propanediamineand 0.77 ml of triethylamine in 5 ml of DCM and left stirring for 2hours at RT. After 2 washes with 20 ml of water and 2 extractions of theaqueous phases with 50 ml of DCM, the DCM phases are washed twice with20 ml of 5% NaHCO₃ and then with 20 ml of water, then dried over MgSO₄and evaporated under vacuum to obtain 2.3 g of expected product (oil).

NMR: 1.9:u.c.:2H; 2.1:s:3H; 2.6:s: 3H; 2.8:s:6H; 2.9-3.2:u.c.:2H;3.45:u.c.: 2H; 3.6:s:6H; 3.8:s:3H; 6.6:d:2H; 6.85:s :1H; 7.05:bs:1H;7.2-7.4:u.c.:3H.

By following the above procedures, the esters of formula IIa describedin Table 3 below are prepared, either from an ester of formula II'asubstituted with R'₁, or by the action of the appropriate hydrazine oncompound A or compound A₁.

                                      TABLE 3                                     __________________________________________________________________________     ##STR67##                                                                    Prepara-                         M.p. °C. or                           tion                             NMR                                          (from)                                                                              R.sub.1 or R'.sub.1 !                                                                      R.sub.2                                                                            R.sub.3                                                                            Alk (Salt)                                       __________________________________________________________________________    3.33 4-CONMe(CH.sub.2).sub.2 NMe.sub.2                                                           2-OCH.sub.3                                                                        H    Me  NMR                                          (3.21)                                                                        3.34 (3.21)                                                                         ##STR68##    2-OCH.sub.3                                                                        H    Me  NMR                                          3.35 4-SO.sub.3 H  2-CH.sub.3                                                                         3-CH.sub.3                                                                         Me  208                                          (2.12)                                                                        3.36 4-SO.sub.2 NMe(CH.sub.2).sub.3 NMe.sub.2                                                    2-CH.sub.3                                                                         3-CH.sub.3                                                                         Me  NMR                                          (3.35)                                                                        3.37 5-CO.sub.2 H  2-Cl H    Et  NMR                                          (2.13)                                                                        3.38 5-CONMe(CH.sub.2).sub.2 NMe.sub.2                                                           2-Cl H    Et  NMR                                          (3.37)                                                                        3.39 4-CO.sub.2 H  2-CF.sub.3                                                                         H    Et  220                                          (2.16)                                                                        3.40 4-CONMe(CH.sub.2).sub.2 NEt.sub.2                                                           2-CF.sub.3                                                                         H    Et  70 (dec.)                                    (3.39)                           NMR                                          3.41 5-CO.sub.2 H  2-OCH.sub.3                                                                        H    Et  NMR                                          (2.14)                                                                        3.42 5-CONMe(CH.sub.2).sub.2 NMe.sub.2                                                           2-OCH.sub.3                                                                        H    Et  NMR                                          (3.41)                                                                        3.43 4-CONH(CH.sub.2).sub.2 N(iPr).sub.2                                                         2-iPr                                                                              H    Me  NMR                                          (3.1)                                                                         3.44 4-CO.sub.2 H  2-iPr                                                                              H    Et  NMR                                          (3.1 a)                                                                       3.45 4-CONH(CH.sub.2).sub.3 N(nBu).sub.2                                                         2-iPr                                                                              H    Et  NMR                                          (3.44)                                                                        3.46 4-CONH(CH.sub.2).sub.2 NEt.sub.2                                                            2-iPr                                                                              H    Et  NMR                                          (3.44)                                                                        3.47 (3.1)                                                                          ##STR69##    2-iPr                                                                              H    Me  100                                          3.48 4-CON(CH.sub.2 CH.sub.2 NEt.sub.2).sub.2                                                    2-iPr                                                                              H    Me  92                                           (3.1)                            2HCl                                         3.49 (3.1)                                                                          ##STR70##    2-iPr                                                                              H    Me  NMR                                          3.50 (3.1)                                                                          ##STR71##    2-iPr                                                                              H    Me  NMR                                          3.51 (3.1)                                                                          ##STR72##    2-iPr                                                                              H    Me  NMR                                          3.52 (3.1)                                                                          ##STR73##    2-iPr                                                                              H    Me  NMR                                          3.53 4-CONMe(CH.sub.2).sub.2 CN                                                                  2-iPr                                                                              H    Me  NMR                                          (3.1)                                                                         3.54 4-CONHCH.sub.2 CHCH.sub.2                                                                   2-iPr                                                                              H    Me  NMR                                          (3.1)                                                                         3.55 (3.12)                                                                         ##STR74##    2-iPr                                                                              H    Me  NMR                                          3.56 4-NO.sub.2    2-Me H    Me  162                                          (2.19)                                                                        __________________________________________________________________________

NMR

Preparation 3.33:2 to 3.8:mt:1H; 3.9:s :3H; 6.6:d:2H; 6.85:s:1H; 6.9 to7.4:u.c.: 4H.

Preparation 3.36 (DMSO+TFA ):1.9:u.c.+s: 5H; 2.5:s:3H; 2.8:s:9H;3-3.5:u.c.:2H; 3.25 t:2H; 3.6:s:6H; 3.85:s:3H; 6.6:d:2H; 6.9:s:1H;7.05-7.15:u.c.:1H; 7.3:t:1H; 7.6:d:1H.

Preparation 3.37:1.2:t:3H; 3.5:s:6H; 4.3:qr:2H; 6.5:d:2H; 6.8:s:1H;7.2:t: 1H; 7.6:d:1H; 7.7:s:1H; 7.85:d:1H.

Preparation 3.38:1.4:t:3H; 1.8 to 3.3: u.c.:13H; 3.65:s:6H; 4.4:qr:2H;6.6:d:2H; 6.95:s:1H; 7.2 to 7.6:u.c.:4H; 7.7:d:1H.

Preparation 3.40:0.6 to 1:u.c. 6H; 1.3:t 3H; 2.2:u.c.:2H; 2.4 to3.4:u.c.:7H; 3.6:s:6H; 4.1:u.c.:2H; 4.3:qd:2H; 6.6:d:2H; 6.8 :s:1H;7.15:u.c.:2H; 7.6:d:1H; 7.8:bs: 1H.

Preparation 3.41:1.4:t:3H; 3.6:s:9H; 4.4:qr:2H; 6.62:d:2H; 6.81:s:1H;7.2:d: 1H; 7.36:t:1H; 7.8:d:1H; 8.0:dd:1H; 12.6: bs:1H.

Preparation 3.42:1.4:t:3H; 1.8 to 2.4: bs:8H; 2.8:bs:3H; 3.2 to3.8:bs:2H; 3.6:s: 9H; 4.4:qd:2H; 6.6:d:2H; 6.8:s:1H; 7.0 to 7.5:u.c. 4H.

Preparation 3.43:1.0-1.1:u.c.:18H; 2.4-2.75:2mt: 3H; 2.9-3.1:mt:2H;3.1-3.35:mt:2H; 3.65:s:6H; 3.9:s:3H; 6.65:d:2H; 6.9:s: 1H;7.3-7.4:mt:2H; 7.7:d:1H; 7.8:s:1H; 8.55 t:1H.

Preparation 3.45:0.75:t:6H; 0.9:d:6H; 1.05-1.15:u.c.:8H; 1.5:t:2H;2.5-2.4:u.c.: 6H; 2.55:sp:1H; 3.15:mt:2H; 3.55:s:6H; 4.2:s: 3H;6.5:d:2H; 6.72:s:1H; 7.1-7.25:u.c.:2H; 7.55:dd:1H; 7.65:d:1H; 8.45:t:1H.

Preparation 3.46:0.8-1.1:u.c.:12H; 1.25: t:3H; 2.4-2.8:u.c.:6H;3.1-3.4:u.c.:3H; 3.5: s:6H; 4.2:qt:2H; 6.5:d:2H; 7.2:u.c.:2H; 7.6:d:1H;7.8:bs:1H; 8.6:bs:1H.

Preparation 3.49:0.9-1.15:2mt:9H; 1.5-1.9 :u.c.:4H; 2.1-2.45:2mt:2H;2.65:mt:1H; 2.75-3: mt:1H; 3-3.2:u.c.:2H; 3.2-3.55:u.c.:2H; 3.65:s:6H;3.9:s:3H; 6.65:d:2H; 6.9:s: 1H; 7.25-7.4:mt:2H; 7.7:d:1H; 7.85:s:1H;8.6:t:1H.

Preparation 3.50:1.05:d:6H; 1.1-1.6: 2s+m:14H; 1.8:dd:2H; 2.65:mt:1H;3.7:s: 6H; 3.9:s:3H; 4.2.-4.5:u.c.:1H; 6.65:d:2H; 6.9:s:1H;7.9.5-7.2:mt:2H; 7.7:d:1H; 7.85: s:1H; 8.3:d:1H.

Preparation 3.51 (DMSO+TFA ):1.0:d:6H; 1.1-1.4:u.c.:6H; 2.0-2.5:u.c.:2H;2.7:2u.c.: 1H; 3.0-4.2:3u.c.+s:18H; 6.7:d:2H; 6.9:s: 1H;7.3-7.55:u.c.:4H.

Preparation 3.52 (DMSO+TFA): 0.95:d:6H; 1.5-1.8:u.c.:2H;1.8-2.2:u.c.:2H; 2.6:mt: 1H; 2.75:s:6H; 2.9-3.8:2u.c.+s:10H; 3.85:s: 3H;4.5-4.7:u.c.:1H; 6.6:d:2H; 6.85:s:1H; 7.2-7.35:mt:4H.

Preparation 3.53 (DMSO+TFA): 0.98:d:6H; 2.6:mt:1H; 2.7-3.8:u.c.:13H;3.82:s:3H; 6.58:d:2H; 6.85:s:1H; 7.15-7.37:u.c.:4H.

Preparation 3.54:1.05:d:6H; 2.7:mt: 1H; 3.7:s:6H; 3.85-4.0:s+mt:5H;5.1-5.3:u.c. :2H; 5.8-6.1:u.c.:1H; 6.55:d:2H; 6.9:s:1H; 7.3-7.4:u.c. 2H;7.75:d:1H; 7.9:s:1H; 8.8:t:1H. 8,8:t:1H.

Preparation 3.55:1.05:d:6H; 2:s:6H; 2.15:t:2H; 2.75:qt:1H; 3.2:t:2H;3.7:s: 6H; 3.9:s:3H; 4.45:s:2H; 6.7:d:2H; 7:s: 1H; 7.3-7.5:u.c.:6H;7.55:d:1H; 7.7-7.9:u.c.:2H.

PREPARATION 3.7

5-(2,6-Dimethoxyphenyl)-1- 4- N-methyl-N- 3-N'-methyl-N'-(tert-butoxycarbonyl)amino!propyl!carbamoyl!-2-isopropylphenyl!-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =4-CONMe(CH₂)₃ N(Me)COOt-Bu; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

A) N-Methyl-N-(3-methylaminopropyl)carbamic acid tert-butyl ester.

A solution of 4.19 g of N,N'-dimethyl-1,3-propanediamine in 80 ml of THFis cooled to 0° C., a solution of 2.68 g of di-tert-butyl dicarbonate in25 ml of THF is added and the mixture is left stirring for 72 hours atRT. Some insoluble matter is filtered off and the filtrate isconcentrated under vacuum. The residue is extracted with DCM, theorganic phase is washed three times with water and dried over MgSO₄ andthe solvent is evaporated off under vacuum. 1.6 g of the expectedproduct are obtained in the form of a yellow oil.

B) 5-(2,6-Dimethoxyphenyl)-1- 4- N-methyl-N- 3-N'-methyl-N'-(tert-butoxycarbonyl)amino!propyl!-carbamoyl!-2-isopropylphenyl!-3-pyrazolecarboxylicacid methyl ester.

A solution of 2.6 g of the compound obtained in step A of Preparation3.2 is added at RT and under a nitrogen atmosphere to a solution of 1.31g of the compound obtained in the preceding step and 0.9 ml oftriethylamine in 4 ml of DCM, and the reaction mixture is left stirringovernight at RT. It is washed twice with water, the organic phase isdried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica, eluting with a toluene/AcOEtmixture from (65:35; v/v) to (60:40; v/v). 2.85 g of the expectedproduct are obtained.

NMR (DMSO+TFA): 1.0:d:6H; 1.4:d:9H; 1.6-1.9:u.c.:2H; 2.7:mt:1H;2.7-3.55:d+bs+u.c.:10H; 3.65:s:6H; 3.9:s:3H; 6.65:d:2H; 6.9:s:1H;7.3-7.45:u.c.:4H.

PREPARATION 3.58

5-(2,6-Dimethoxyphenyl)-1-4-(4-methylphenyl-sulphonylamino)-2-isopropylphenyl!-3-pyrazolecarboxylicacid ethyl ester. ##STR75##

A mixture of 3.44 g of the compound obtained in Preparation 2.18 and 2.6g of compound A₁ in 50 ml of acetic acid is heated for 1 hour at 70° C.The reaction mixture is poured into water, the resulting mixture isextracted with AcOEt, the organic phase is dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H, eluting with a DCM/MeOH (100:0.5; v/v) mixture. 1.26 g ofthe expected product are obtained.

NMR: 0.7:d:6H; 1.22:t:3H; 2.2-2.5: u.c.:4H; 3.45:s:6H; 4.2:t:2H;6.46:d:2H; 6.69:s:1H; 6.75-6.9:u.c.:2H; 7.0:d:1H; 7.15-7.3:u.c.:3H;7.5:d:2H; 10.2:s:1H.

PREPARATION 3.59

5-(2,6-Dimethoxyphenyl)-1- 4-4-methylphenyl-sulphonyl-N-(3-diethylaminopropyl)amino!-2-isopropyl-phenyl!-3-pyrazolecarboxylicacid ethyl ester. ##STR76##

A mixture of 0.65 g of the compound obtained in 30 Preparation 3.58,0.338 g of (3-chloropropyl)diethylamine and 0.65 g of K₂ CO₃ in 5 ml ofDMF is heated at 80° C. for 2 hours. The reaction mixture is poured intowater, the resulting mixture is extracted with AcOEt, the organic phaseis dried over Na₂ SO₄ and the solvent is evaporated off under vacuum.The residue is chromatographed on silica H, eluting with a DCM/MeOH(100:5; v/v) mixture. 0.57 g of the expected product is obtained.

NMR: 0.8:bs:6H; 0.95:t:6H; 1.4:t: 3H; 1.5:qt:2H; 2.3-2.65:u.c.:10H;3.5-3.8: u.c.:8H; 4.35:qr:2H; 6.7:d:2H; 6.75:d:1H; 6.9:s:1H; 7.05:dd:1H;7.2-7.6:u.c.:6H.

PREPARATION 3.60

5-2-(Cyclopropylmethyloxy)-6-methoxyphenyl!-1-(4-carboxy-2-isopropylphenyl)-3-pyrazolecarboxylicacid ethyl ester. ##STR77##

A mixture of 5.26 g of the compound obtained in Preparation 1.2 and 3.9g of the compound obtained in Preparation 2.1 in 50 ml of acetic acid isheated at 80° C. for 8 hours. The reaction mixture is poured into awater/ice mixture, and the precipitate formed is drained and washed withwater and then with pentane. The precipitate is taken up with tolueneand the solvent is evaporated off under vacuum. 5.2 g of the expectedproduct are obtained.

PREPARATION 3.61

5- 2-(Cyclopropylmethyloxy)-6-methoxyphenyl!-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolecarboxylicacid ethyl ester. ##STR78##

This compound is prepared according to the procedures described in stepsA and B of Preparation 3.2, from 5.2 g of the compound obtained inPreparation 3.60 and 2.4 ml of SOCl₂, followed by 1.39 g ofN,N,N'-trimethyl-1,3-propanediamine and 1.5 ml of triethylamine in 10 mlof toluene. The product is purified by chromatography on silica, elutingwith DCM and then with a DCM/MeOH (88:2; v/v) mixture. 3.8 g of theexpected product are obtained.

PREPARATION 3.62

5-(2,6-Dimethoxyphenyl)-1-4-(4-methylphenyl-sulphonylamino)-2-isobutylphenyl!-3-pyrazolecarboxylicacid methyl ester. ##STR79##

A mixture of 1.9 g of the compound obtained in Preparation 2.20 and 1.6g of the compound A in 30 ml of acetic acid is heated to reflux for 45minutes. After cooling to RT, the reaction mixture is poured into water,and the precipitate formed is drained and dried. 1 g of the expectedproduct are obtained after recrystallization in 2-propanol, m.p.=224° C.

NMR: 0.55:d:6H; 1.5:mt:1H; 1.9:d: 2H; 2.3:s:3H; 3.45:s:6H; 3.8:s:3H;6.5:d 2H; 6.75:s:1H; 6.8:d:1H; 6.9:dd:1H; 7.05 d:1H; 7.15-7.7:u.c.:5H;10.25:s:1H.

PREPARATION 3.63

5-(2,6-Dimethoxyphenyl)-1-4-(4-methylphenyl-sulphonylamino)-2-cyclopentylphenyl!-3-pyrazolecarboxylicacid methyl ester. ##STR80##

A mixture of 2.42 g of the compound obtained in Preparation 2.21 and2.92 g of compound A in 50 ml of acetic acid is heated for 1 hour at 80°C. The reaction mixture is poured into water, the resulting mixture isextracted with AcOEt, the organic phase is dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H, eluting with a DCM/MeOH (100:1; v/v) mixture. 0.95 g of theexpected product are obtained after trituration in ether, m.p.=200-230"C.

NMR: 1.0-1.8:u.c.:8H; 2.37:s:3H; 3.1-3.7:u.c.:7H; 3.82:s:3H; 6.55:d:2H;6.79:s 1H; 6.85-7.0:u.c.:2H; 7.05:d:2H; 7.21-7.42: u.c.:3H; 7.58:d:2H;10.3:s:2H.

PREPARATION 3.64

5-(2,6-Dimethoxyphenyl)-1-(4-carboxy-3-isopropyl-phenyl)-3-pyrazolecarboxylicacid ethyl ester.

(II'a:R'₁ =4-CO₂ H; R₂ =3-iPr; R₃ =H; R₄ =Me).

A mixture of 0.36 g of the compound obtained in Preparation 2.22 and0.48 g of compound A₁ in 10 ml of acetic acid is heated to reflux for 5hours. The reaction mixture is poured into 160 ml of ice-cold water, andthe precipitate formed is drained, washed with water and dried. 0.52 gof the expected product is obtained, m.p.=180° C. (dec.).

PREPARATION 3.65

1- 4-N-(2-Diethylaminoethyl)carbamoyl!-3-iso-propylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazole-carboxylicacid ethyl ester.

(IIa:R₁ =4-CONH(CH₂)₂ NEt₂ ; R₂ =3-iPr; R₃ =H; R₄ =Me).

This compound is prepared according to the procedure described in stepsA and B of Preparation 3.2, from 0.5 g of the compound obtained inPreparation 3.64 and 5 ml of SOCl₂ in 20 ml of chloroform, followed by0.2 ml of N,N-diethylethylenediamine and 0.8 ml of triethylamine in 20ml of chloroform. 0.37 g of the expected product is obtained aftercrystallization in AcOEt, m.p.=130° C. (dec.).

PREPARATION 3.66

5-(2,6-Dimethoxyphenyl)-1-(4-nitro-5,6,7,8-tetra-hydro-1-naphthyl)-3-pyrazolecarboxylicacid methyl ester.

(II'a:R'₁ =4-NO₂ ; R₂, R₃ =--(CH₂)₄ -; R₄ =Me).

A mixture of 6.3 g of the compound obtained in Preparation 2.23 and 7.45g of compound A in 150 ml of acetic acid is heated to reflux for 2hours. After cooling to RT, 100 ml of water and 30 ml of MeOH are addedand the crystallized product is drained. 4.6 g of the expected productare obtained, m.p.=212° C.

NMR: 1.7:mt:4H; 2.55:mt:2H; 2.82:mt 2H; 3.65:s:6H; 3.85:s:3H; 6.65:d:2H;6.9:s:1H; 7.02:d:1H; 7.33:t:1H; 7.67:d:1H.

PREPARATION 3.67

5-(2,6-Dimethoxyphenyl)-1-(5-(3-(diethylamino)-propanoylamino)-2-isopropylphenyl)-3-pyrazolecarboxylicacid methyl ester.

(IIa:R₁ =5-NHCO(CH₂)₂ NEt₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

This compound is obtained from the hydrazine of Preparation 2.24.

NMR (DMSO+TFA): 0.65-1.35:u.c.:12H; 2.5:qt:1H; 2.8:t:2H; 3.15:qr:4H;3.36:t: 3.57:s:6M; 3.8:s:3H; 6.5:d:2H; 6.78:s: 1H; 7.1-7.4:u.c.:3H;7.8:d:1H.

PREPARATIONS OF THE ACIDS II, II' PREPARATION 4.1

1- 4-N-Methyl-N-(3-(N',N'-dimethylamino)propyl)-carbamoyl!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid.

(II, R₁ =4-CONMe(CH₂)₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

23 g of the compound obtained in Preparation 3.2 in 230 ml of dioxaneand 6.2 g of potassium hydroxide in 6 ml of water are mixed. The mixtureis heated to reflux for three and a half hours. After cooling, it isevaporated, the residue is redissolved in the minimum amount of waterand the mixture is washed three times with ether and then acidified topH 4 by adding concentrated HCl; the aqueous phase is evaporated, theresidue is then redissolved in the minimum amount of EtOH and the KCl isfiltered off (twice). After evaporation, 23.93 g of the expected productare obtained in the form of a light yellow foam, m.p.=128° C. (dec.).

NMR: 0.95:d:6H; 1.95:mt:2H; 2.45-3.3:u.c.:12H; 3.35-3.8:u.c.:8H;6.6:d:2H; 6.8:s 1H; 7-7.5:u.c.:4H.

PREPARATION 4,1a

1- 4-N-Methyl-N-(3-(N',N'-dimethylamino)propyl)-carbamoyl!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid potassium salt.

A solution of 8.07 g of KOH in 133 ml of water is added to a solution of26.6 g of the product of Preparation 3.2a in 133 ml of ethanol. Thesolution is stirred for 8 hours, then left stirring for 15 hours andevaporated under vacuum to obtain the expected potassium salt.

PREPARATION 4.2

1- 4-N-(2-Cyanoethyl)carbamoyl!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid.

(II:R₁ =4-CONHCH₂ CH₂ CN; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

A solution of 0.9 g of KOH in 3 ml of water is added to a solution of3.04 g of the compound obtained in Preparation 3.3 in 30 ml of1,4-dioxane and a few drops of MeOH, and the mixture is left stirringover-night at RT. It is concentrated under vacuum, the residue is takenup with water, the aqueous phase is washed with ether, acidified to pH 2by adding 10% HCl and extracted with DCM, the organic phase is driedover Na₂ SO₄ and the solvent is evaporated off under vacuum. 2.93 g ofthe expected product are obtained, m.p.=128° C. (dec.).

NMR: 1:d:6H; 2.65:mt:1H; 2.8:t:2H; 3.5:t:2H; 3.6:s:6H; 6.6:d:2H;6.8:s:1H; 7.2-7.4:u.c.:2H; 7.7:dd:1H; 7.8:d:1H.

From the esters of formula (IIa) described in Table 2, and by workingaccording to the procedure described in Preparation 4.1 or Preparation4.2, the acids of formula (II) described in Table 4 below are obtained.

                  TABLE 4                                                         ______________________________________                                         ##STR81##                                                                    Preparation                                                                           R.sub.1              M.p. °C. or NMR                           ______________________________________                                        4.3     CONH(CH.sub.2).sub.3 NMe.sub.2                                                                     188                                                                           NMR                                              4.4     CONH(CH.sub.2).sub.2 NMe.sub.2                                                                     178-180 (dec.)                                                                NMR                                              4.5     CONH(CH.sub.2).sub.3 NEt.sub.2                                                                     NMR                                              4.6                                                                                    ##STR82##           NMR                                              4.7                                                                                    ##STR83##           NMR                                              4.8                                                                                    ##STR84##           135 (dec.) NMR                                   4.9                                                                                    ##STR85##           NMR                                              4.10                                                                                   ##STR86##           266 (dec.)                                       ______________________________________                                    

PREPARATION 4.3

NMR: 0.9:d:6H; 1.6:mt:2H; 2.15:s: 6H; 2.35:t:2H; 2.6:mt:1H; 3.2:u.c.:2H;3.55 s:6H; 6.5:d:2H; 6.6:s:1H; 7.1-7.2:u.c.: 2H; 7.7:dd:1H; 7.9:bs:1H;8.6:t:1H.

PREPARATION 4.4

NMR (DMSO+TFA): 1:d:6H; 2.65:mt:1H; 2.85:s:6H; 3.3:mt:2H; 3.6:mt+s:8H;6.6:d:2H; 6.8:s:1H; 7.25-7.4:u.c.:2H; 7.7:dd:1H; 7.85:bs:

PREPARATION 4.5

NMR: 0.95:d:6H; 1.15:t:6H; 1.8-2: u.c. 2H; 2.6:mt:1H; 3.1:mt:4H;3.3:t:2H; 3.6:u.c.+s:8H; 6.5:d: 2H; 7.6:dd:1H; 7.75:d:1H.

PREPARATION 4.6

NMR (DMSO+TFA): 1:d:6H; 1.8-2.2:u.c.: 4H; 2.65:mt:1H; 3:mt:2H;3.3:mt:2H; 3.6: bs:10H; 6.6:d:2H; 6.8:s:1H; 7.2-7.4:u.c.: 2H;7.6-7.9:u.c.:2H; 8.9:t:1H.

PREPARATION 4.7

1.1:d:6H; 2.7:mt:1H; 3.7:s:6H; 6.65:D:2H; 6.9:s:1H; 7.2-7.4:u.c.:3H;7.8-8.5:m:5H.

PREPARATION 4.8

NMR: 1-1.2:m:12H; 2.6-2.9:u.c.:9H; 3.3:d:2H; 3.7:s:6H; 6.6:d:2H;6.8:s:1H; 7.3-7.4:u.c.:2H; 7.7-7.9:u.c.:2H; 8.8:t:1H.

PREPARATION 4.9

NMR (DMSO+TFA): 1:d:6H; 1.8:mt:2H; 2.1:mt:2H; 2.7:mt:1H; 3-3.5:u.c.:4H;3.6: s:6H; 4:mt:1H; 4.3:s:2H; 6.6:d:2H; 6.8: s:1H; 7.2-7.4:u.c.:2H;7.4-7.6:u.c.:5H; 7.7: d:1H; 7.8:s:1H.

PREPARATION 4.11

5-(2,6-Dimethoxyphenyl)-1-2-isopropyl-4-(N-methyl-N-(3-(N',N'-dimethylamino)propyl)aminosulphonyl)-phenyl!-3-pyrazolecarboxylicacid.

(II: R₁ =4--SO₂ NMe(CH₂ ₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

A mixture containing 1.1 g of the ester obtained in Preparation 3.13 and280 mg of potassium hydroxide in 10 ml of water is left stirring forhours at RT. The reaction medium is concentrated under vacuum until 5 mlare obtained, and the residue is then stirred in the presence of 100 mlof ether and 3 ml of water. The aqueous phase is neutralized to pH 6 byadding 1N HCl; it is filtered, and the residue is then dried over P₂ O₅to obtain 860 mg of the expected product.

NMR: 0.85:d:6H; 1.5:mt:2H; 2.15:s: 6H; 2.3:t:2H; 2.6:s+mt:4H; 2.9:t:2H;3.5: s:6H; 6.5:d:2H; 6.7:s:1H; 7.2:t:1H; 7.4: d:1H; 7.5-7.6:u.c.:2H.

PREPARATION 4.12

5-(2,6-Dimethoxyphenyl)-1- 4- N-3-(N',N'-dimethylamino)propyl!carbamoyl!-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolecarboxylicacid.

(II:R₁ =4-CONH(CH₂)₃ NMe₂ ; R₂, R₃ =--(CH₂)₄ -; R₄ =CH₃).

A mixture of 0.98 g of the compound obtained in Preparation 3.15 and0.16 g of LiOH in 5 ml of methanol and 1 ml of water is heated for 3hours at 40° C. It is evaporated under vacuum, and the residue isneutralized to pH 6 with 1N HCl and then extracted with DCM. The organicphase is dried over MgSO₄ and evaporated under vacuum to obtain 0.47 gof expected product.

NMR: 1.5-2.1:u.c.:6H; 2.3-4:u.c.:2OH; 6.5-7.6:u.c.:6H; 8.4:t:1H.

PREPARATION 4.13

5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-dimethylamino)ethyl)aminosulphonyl!-5,6,7,8-tetrahydro-1-naphthyl}-3-pyrazolecarboxylicacid potassium salt.

(II:R₁ =4-SO₂ NMe(CH₂)₂ NMe₂ ; R₂, R₃ =--(CH₂)₄ -; R₄ =Me).

A solution of 0.87 g of ester obtained in Preparation 3.17 in 5 ml ofdioxane is left stirring for 8 hours at RT with 320 mg of KOH in 0.5 mlof water. The mixture is evaporated under vacuum and the residue isextracted with a mixture of 10 ml of water, 5 ml of ethanol and 100 mlof ether. After decantation, the gum obtained is triturated three timesin ether; the product crystallizes. It is filtered off to obtain 0.9 gof the expected salt.

PREPARATION 4.14

5-(2,6-Dimethoxyphenyl)-1-(4-carbamoyl-2-methyl-phenyl)-3-pyrazolecarboxylicacid.

(II:R₁ =4-CONH₂ ; R₂ =2-CH₃ ; R₃ =H; R₄ =CH₃).

A solution containing 0.4 g of the compound obtained in Preparation 3.18in 5 ml of dioxane and 220 mg of KOH in 1 ml of water is left stirringat RT for 2 hours. It is acidified to pH 1 by adding concentrated HCland then concentrated under vacuum. 5 ml of water are added, the gumformed is then stirred with 50 ml of DCM and the precipitate formed isfiltered off. 330 mg of the expected product are obtained, m.p.=275-276°C.

NMR: 2.05:s:3H; 3.55:s:6H; 6.55:d: 2H; 6.7:s:1H; 7:d:1H; 7.2:t:1H;7.4:bs: 1H; 7.55:d:1H; 7.7:s:1H; 7.9:bs:1H.

PREPARATION 4.15

5-(2,6-Dimethoxyphenyl)-1-{2,3-dimethyl-4-N-(2-(N',N'-dimethylamino)ethyl)carbamoyl!phenyl}-3-pyrazolecarboxylicacid.

(II: R₁ =4-CONH(CH₂)₂ NMe₂ ; R₂ =2-CH₃ ; R₃ =3-CH₃ ; R₄ =CH₃).

A solution of 1.8 g of the product of Preparation 3.20 and 0.32 g ofLiOH in 10 ml of MeOH and 2 ml of water is left stirring for 2 hours at40° C. The pH is adjusted to 6 with 1N HCl and the mixture is evaporatedunder vacuum. After extraction of the residue with 50 ml of DCM andevaporation, 1.3 g of expected product are obtained.

NMR: 1.9:s:3H; 2.2:s+s:9H; 2.5:t: 2H; 3.4:qd:2H; 3.7:s:6H;6.6-6.7:u.c.:3H; 6.9-7.1:u.c.:2H; 7.3:t:1H; 8.3:t:1H.

PREPARATION 4.16

5-(2,6-Dimethoxyphenyl)-1-{4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carbamoyl!-2-methoxyphenyl}-3-pyrazolecarboxylicacid.

(II: R₁ =4-CONMe(CH₂)₂ NEt₂ ; R₂ =2-0CH₃ ; R₃ =H; R₄ =CH₃).

A mixture of 1.73 g of the product of Preparation 3.22 and 0.3 g of LiOHin 400 ml of MeOH and 6 ml of water is left stirring under reflux for 6hours, and then acidified to pH 2 with concentrated HCl. Afterevaporation under vacuum and stirring of the residual oil for 30 minutesat RT with 400 ml of chloroform, and after settling has taken place,separation and drying of the organic phase over Na₂ SO₄ and evaporation,1.2 g of expected product are obtained.

NMR: 1.05-1.4:mt:6H; 3:bs:3H; 3.1-3.9:mt:13H; 6.6:d:2H; 6.8:s:1H;7-7.4:mt: 4H.

PREPARATION 4.17

5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carbamoyl!-2-chlorophenyl}-3-pyrazolecarboxylicacid.

(II: R₁ =4-CONMe(CH₂)₂ NEt₂ ; R₂ =2-Cl; R₃ =H; R₄ =CH₃).

A mixture of 2.6 g of the product of Preparation 3.24 dissolved in 100ml of ethanol and 0.53 g of KOH in 15 ml of water is left stirring for 3days at RT. After acidification to pH 3 with concentrated HCl,evaporation under vacuum, trituration of the residue in 10 ml of water,filtration and drying under vacuum over P₂ O₅, 1.55 g of expectedproduct are obtained.

PREPARATION 4.18

5-(2,6-Dimethoxyphenyl)-1-4-(N-(2-morpholino-ethyl)carbamoyl)-2-chlorophenyl!-3-pyrazolecarboxylicacid. ##STR87##

A solution of 1.5 g of the product of Preparation 3.25 in 75 ml ofethanol is heated with stirring for 1 hour at 60° C. with a solution of0.38 g of KOH in 10 ml of water. After acidification to pH 4.5 withconcentrated HCl and evaporation under vacuum, 4 g of mixture of theexpected product and KCl are obtained.

NMR (DMSO+TFA): 2.9-4:mt:H; 6.5:d: 2H; 6.8:s:1H; 7.1-7.4:mt:2H;7.8:dd:1H; 8: d:1H; 9.1:bs:1H.

PREPARATION 4.19

5-(2,6-Dimethoxyphenyl)-1-(3-chloro-4-cyano-phenyl)-3-pyrazolecarboxylicacid.

(II':R₁ =4-CN; R₂ =3-Cl; R₃ =H; R₄ =CH₃).

A mixture containing 0.5 g of the compound obtained in Preparation 3.26and 60 mg of LiOH in 5 ml of aqueous methanol is heated on a water bathfor 3 hours. After cooling, the pH is lowered to 5 by adding 1N HCl. Theprecipitate formed is filtered off and dried to obtain 0.36 g of theexpected compound.

PREPARATION 4.20

5-(2,6-Dimethoxyphenyl)-1-(4-carbamoyl-3-chloro-phenyl)-3-pyrazolecarboxylicacid.

(II: R₁ =4-CONH₂ ; R₂ =3-Cl; R₃ =H; R₄ =CH₃).

A mixture containing 0.87 g of the compound obtained in Preparation4.19, 390 mg of K₂ CO₃ and 0.4 ml of 30% hydrogen peroxide in 5 ml ofDMSO is left stirring at RT for 24 hours. It is acidified to pH 3 byadding 1N HCl, water is then added, and the precipitate formed isfiltered off and dried to obtain 0.73 g of the expected product.

PREPARATION 4.21

5-(2,6-Dimethoxyphenyl)-1-(4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carbamoyl!-2-cyclopropyl-phenyl}-3-pyrazolecarboxylicacid.

(II: R₁ =4-CONMe(CH₂)₂ NEt₂ ; R₂ =2-cyclopropyl; R₃ =H; R₄ =CH₃).

A solution of 1.29 g of the product of Preparation 3.28 in 26 ml ofethanol is left stirring for 22 hours at RT with a solution of 0.33 g ofKOH in 4 ml of water. After acidification to pH 3 with concentrated HCl,evaporation and azeotropic distillation with 100 ml of toluene and thenwith 100 ml of pentane, the residue is triturated in pentane, filteredoff and dried to obtain 1.4 g of mixture of the expected product withKCl.

NMR: 0.4-1.2:mt:14H; 1.5:u.c.:1H; 2.1-3.8:mt:13H; 6.5:d:2H; 6.7:bs:2H;7:s:2H; 7.2:t:1H.

PREPARATION 4.22

5-(2,6-Dimethoxyphenyl)-1-{3-N-methyl-N-(2-(N',N'-dimethylamino)ethyl)carbamoyl!-4-chlorophenyl}-3-pyrazolecarboxylicacid.

(II: R₁ =3-CONMe(CH₂)₂ NMe₂ ; R₂ =4-Cl; R₃ =H; R₄ =CH₃).

A solution of 0.8 g of the product of Preparation 3.30 in 10 ml ofdioxane is left stirring for 6 hours at RT with 0.22 g of KOH in 2 ml ofH₂. After evaporation under vacuum, the residue is dissolved in 5 ml ofwater, and the mixture is neutralized to pH 5 with concentrated HCl andthen saturated with NaCl. It is extracted twice with 100 ml of DCM, andthe organic phase is dried over Na₂ SO₄ and evaporated under vacuum toobtain 0.43 g of expected product.

NMR: 1.9-3.15:u.c.:13H; 3.6:s:6H; 6.75:d:2H; 6.85:ss:1H;7.1-7.35:u.c.:2H; 7.45: t:1H; 7.57:d:1H.

PREPARATION 4.23

5-(2,6-Dimethoxyphenyl)-1-{5-N-methyl-N-(3-(N',N'-dimethylamino)propyl)carbamoyl!-2-methyl-phenyl}-3-pyrazolecarboxylicacid.

(II: R₁ =5-CONMe(CH₂)₃ NMe₂ ; R₂ =2-CH₃ ; R₃ =H; R₄ =CH₃).

A solution of 2.28 g of the product of Preparation 3.32 in 10 ml ofdioxane is left stirring for 15 hours at RT with a solution of 0.65 g ofKOH in 1.5 ml of water; the mixture is evaporated under vacuum, and theresidue is then dissolved in 20 ml of water and extracted 3 times with50 ml of ether. After acidification of the aqueous phase to pH 4 byadding 1N HCl, and azeotropic distillation with ethanol, the residue istriturated with 20 ml of ethanol, KCl is filtered off and the filtrateis then evaporated under vacuum. This removal of KCl is repeated, andthe mixture is evaporated under vacuum to obtain 2 g of the expectedproduct.

NMR: 1.9:u.c.:2H; 2.2:s:3H; 2.4-3:u.c.:11H; 3.5:mt:2H; 3.65:s:6H;6.65:d:2H; 6.85:s:1H; 7.1:bs:1H; 7.3-7.5:u.c.:3H.

By following the above procedures, the acids of formula II described inTable 5 below are prepared.

                  TABLE 5                                                         ______________________________________                                         ##STR88##                                                                    Prepara-                              M.p. °C.                         tion                                  or                                      from   R.sub.1          R.sub.2 R.sub.3                                                                             NMR                                     ______________________________________                                        4.24   4-CONMe(CH.sub.2).sub.2 NMe.sub.2                                                              2-OCH.sub.3                                                                           H     NMR                                     (3.33)                                                                        4.25 (3.34)                                                                           ##STR89##       2-OCH.sub.3                                                                           H     NMR                                     4.26   4-SO.sub.2 NMe(CH.sub.2).sub.3 NMe.sub.2                                                       2-CH.sub.3                                                                            3-CH.sub.3                                                                          NMR                                     (3.36)                                                                        a) 4.27                                                                              5-CONMe(CH.sub.2).sub.2 NMe.sub.2                                                              2-Cl    H     NMR                                     (3.38)                                                                        4.28   4-CONMe(CH.sub.2).sub.2 NEt.sub.2                                                              2-CF.sub.3                                                                            H     NMR                                     (3.40)                                                                        a) 4.29                                                                              5-CONMe(CH.sub.2).sub.2 NMe.sub.2                                                              2-OCH.sub.3                                                                           H     NMR                                     (3.42)                                                                        4.30   4-CONH(CH.sub.2).sub.2 N(iPr).sub.2                                                            2-iPr   H     NMR                                     (3.43)                                                                        a) 4.31                                                                              4-CONH(CH.sub.2).sub.3 N(nBu).sub.2                                                            2-iPr   H     NMR                                     (3.45)                                                                        a) 4.32                                                                              4-CONH(CH.sub.2).sub.2 NEt.sub.2                                                               2-iPr   H     NMR                                     (3.46)                                                                        4.33 (3.47)                                                                           ##STR90##       2-iPr   H     NMR                                     4.34   4-CON(CH.sub.2 CH.sub.2 NEt.sub.2).sub.2                                                       2-iPr   H     NMR                                     (3.48)                                                                        4.35 (3.49)                                                                           ##STR91##       2-iPr   H     NMR                                     4.36 (3.50)                                                                           ##STR92##       2-iPr   H     NMR                                     4.37 (3.52)                                                                           ##STR93##       2-iPr   H     196                                     4.38   4-CONMe(CH.sub.2).sub.2 CN                                                                     2-iPr   H     178-180                                 (3.53)                                NMR                                     4,39 (3.55)                                                                           ##STR94##       2-iPr   H     140                                     ______________________________________                                         The letter a) indicates that the potassium salt of the acid of the formul     II was obtained.                                                         

NMR:

Preparation 4.24 (DMSO):2:u.c.:2H; 2.5:u.c.:6H; 2.8-3.5:u.c.:5H;3.5:s:3H; 3.6:s:6H; 6.6:d:2H; 6.8:s:1H; 7.05:u.c.:2H; 7.15 u.c.:2H.

Preparation 4.25 :2. 1:s:3H; 2.3:u.c.:4H; 3.1 to 3.7:u.c.:13H; 6.5:d:2H;6.7:s:1H; 6.9:u.c.:2H; 7.25:u.c.:2H.

Preparation 4.27:1.6-3.2:u.c.:13H; 3.6:s:6H; 6.4:s:1H; 6.6.:d:2H;7-8:u.c.:4H.

Preparation 4.28:0.9:u.c.:6H; 2-3.4:u.c.:11H; 3.5:s:6H; 6.4:s:1H;6.6:d:2H; 7.15:u.c.:2H; 7.75:d:14H; 7.85:bs:1H.

Preparation 4.29:1.8-2.6:u.c.:8H; 2.8: bs:3H; 3.4-3.8:bs:2H; 3.6:s:6H;3.64:s:3H; 6.50:s:1H; 6.60:d:2H; 7-7.50:u.c.:4H.

Preparation 4.30 (DMSO+TFA): 1:d:6H; 1.3:d:12H; 2.65:mt:1H; 3.2:t:2H;3.5-3.75:u.c.:+s:10H; 6.55:d:2H; 6.8:s:1H; 7.2-7.35:mt:2H; 7.7:d:1H;7.8:s:1H.

Preparation 4.31:0.8:t:6H; 0.95:d:6H; 1.1-1.4:u.c.:8H; 1.58:t:2H;2.15-2.4:u.c.:6H; 2.55:sp:1H; 3.2:mt:2H; 3.57:s:6H; 6.3:s:1H; 6.5:d:2H;7.1-7.3:u.c.:2H; 7.74:dd:1H; 7.75:d:1H; 8.45:t:1H.

Preparation 4.32:0.9-1.1:u.c.:12H; 2.6:u.c.:6H; 2.7:u.c.:1H;3.2-3.4:u.c.:2H; 3.6:u.c.:6H; 6.3:s:1H; 6.6:d:2H; 7.1-7.3:u.c.:2H;7.6-7.8:u.c.:2H.

Preparation 4.33:1:d:6H; 1.5-1.9:u.c.:6H; 2-2.2:u.c.:2H; 2.2:s:6H;2.7:s:2H; 2.8 qt:1H; 3.6:s:6H; 6.45:s:1H; 6.6:d:2H; 7.2-7.35:u.c.:2H;7.6:d:1H; 7.7:s:1H; 7.9: s:1H.

Preparation 4.34:1:m:12H; 1.3:mt:6H; 2.5-3.9:u.c.+s:23H; 6.6:d:2H;6.8:s:1H; 7.2-7.4:u.c.:3H; 7.55:s:1H.

Preparation 4.35 (DMSO+TFA): 1:u.c.:6H; 1.2:t:3M; 1.75-2.2:2u.c.:4H;2.65:mt:1H; 3:u.c.:2H; 3.4-3.7:u.c.+s:11H; 6.5:d:2H; 6.75:s:1H;7.2:t:1H; 7.3:d:1H; 7.65:d:1H; 7.8:s:1H.

Preparation 4.36:1.05:d:6H; 1.5:s: 12H; 1.7:t:2H; 2.0:d:2H; 2.7:mt:1H;3.7:s 6H; 4.3-4.5:u.c.:1H; 6.7:d:2H; 6.85:s:1H; 7.25-7.4:mt:2H;7.75:d:1H; 7.9:s:1H; 8.3-8.5:u.c.:1H; 8.7:d:1H; 12.8:u.c.:1H.

Preparation 4.38:0.95:d:6H; 2.6:mt:1H; 2.7-3.8:u.c.:13H; 6.57:d:2H;6.75:s:1H; 7.12-7.35:u.c.:4H; 12.7:bs:1H.

PREPARATION 4.40

1- 4- N-Ethyl-N-(2-N',N'-diethylaminoethyl)carbamoyl!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylic acid.

(II: R₁ =4-CONEt(CH₂)₂ NEt₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

A solution of 0.48 g of the compound obtained in Preparation 4.32 and0.28 ml of ethyl iodide in 3 ml of THF is cooled to 5° C., 0.063 g of60% sodium hydride in oil is then added portionwise and the mixture isleft stirring for 24 hours at RT. 0.48 ml of a THF/water (50:50; v/v)mixture is added and the reaction mixture is concentrated under vacuum.The residue is taken up with water, the aqueous phase is washed twicewith pentane, acidified to pH 1 by adding 1N HCl solution and extractedwith AcOEt and then with DCM, the organic phases are dried over Na₂ SO₄and the solvents are evaporated off under vacuum. 0.14 g of the expectedproduct is obtained.

NMR (DMSO+TFA): 0.8-1.3:u.c.:15H; 2.6:u.c.:1H; 3.0-3.8:u.c.:16H;6.5:d:2H; 6.75:s 1H; 7.2:u.c.:4H.

PREPARATION 4.41

1- 4-3-(Diethylamino)-1-pyrrolidinyl!carbonyl!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazole-carboxylicacid hydrochloride. ##STR95##

A solution of 0.11 g of KOH in 0.5 ml of water is added at RT to asolution of 0.44 g of the compound obtained in Preparation 3.51 in 4 mlof dioxane, and the mixture is left stirring overnight at RT. It isconcentrated under vacuum, the residue is taken up with water, theaqueous phase is washed twice with ether and acidified to pH 2 by adding1.2N HCl, EtOH is added and the mixture is concentrated under vacuum.The residue is taken up with EtOH, the KCl is filtered off and thefiltrate is concentrated under vacuum. 0.39 g of the expected product isobtained.

NMR (DMSO+TFA): 1.0:d:6H; 1.15-1.35: u.c.:6H; 2.1-2.45:u.c.:2H;2.65:mt:1H; 2.9-4.1:3u.c.+s:15H; 6.6:d:2H; 6.8:s:1H; 7.2-7.5:mt:3H;7.55:s:1H.

PREPARATION 4.42

1- 4-N-(2-Propenyl)carbamoyl!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid.

(II: R₁ =4-CONHCH₂ CH=CH₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

A mixture of 1.72 g of the compound obtained in Preparation 3.54 and0.78 g of LiOH.H₂ O in 10 ml of MeOH and 1 ml of water is left stirringfor 7 hours at RT. It is concentrated under vacuum, the residue is takenup with water, the aqueous phase is washed twice with ether, acidifiedto pH 2-3 by adding 1.2N HCl and extracted with DCM, the organic phaseis dried over MgSO₄ and the solvent is evaporated off under vacuum. 1.64g of the expected product are obtained.

NMR: 1.0:d:6H; 2.7:qt:1H; 3.7:s: 6H; 3.95:t:2H; 5.1-5.3:u.c.:2H;5.8-6.1:u.c.: 1H; 6.65:d:2H; 6.85:s:1H; 7.25-7.4:u.c.: 2H; 7.75:d:1H;7.9:s:1H; 8.8:t:1H.

PREPARATION 4.43

1- 4- N-Methyl-N- 3-N'-methyl-N'-(tert-butoxy-carbonyl)amino!propyl!carbamoyl!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid.

(II: R₁ =4-CONMe(CH₂)₃ N(Me)COOt-Bu; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

A mixture of 2.85 g of the compound obtained in

Preparation 3.57 and 0.98 g of LiOH.H₂ O in 20 ml of MeOH and 1 ml ofwater is left stirring for 3 hours 30 minutes at RT. It is concentratedunder vacuum, the residue is taken up with water and acidified to pH 2by adding a pH 2 buffer solution, and the precipitate formed is drainedand washed with water. 2.47 g of the expected product are obtained afterdrying over P₂ O₅, m.p.=112°-114° C.

PREPARATION 4.44

1-4-(4-Methylphenylsulphonylamino)-2-isopropyl-phenyl!-5-(2,6-dimethoxyphenyl!-3-pyrazolecarboxylicacid. ##STR96##

A mixture of 1.05 g of the compound obtained in Preparation 3.58 and0.33 g of LiOH.H₂ O in 5 ml of MeOH and 0.5 ml of water is heated for 3hours at 60° C. The reaction mixture is poured into water, the resultingmixture is acidified to pH 2-3 by adding 10% HCl solution, and theprecipitate formed is drained and dried. 0.92 g of the expected productis obtained.

NMR: 0.7:d:6H; 2.3-2.6:u.c.:4H; 3.55: s:6H; 6.6:d:2H; 6.75:s:1H;6.85-7.01:u.c.: 2H; 7.11:d:1H; 7.25-7.42:u.c.:3H; 7.6:d:2H; 10.3:s:1H;12.75:bs:1H.

PREPARATION 4.45

1-(4-Amino-2-isopropylphenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylicacid.

(II':R'₁ =4-NH₂ ; R₂ =2-iPr; R₃ =H; R₄ =Me).

A mixture of 0.9 g of the compound obtained in Preparation 3.58, 11 mlof acetic acid and 25 ml of 70% perchloric acid is heated to reflux for10 minutes. The reaction mixture is poured into a water/ice mixture,some insoluble matter is filtered off, the filtrate is taken to pH 5 byadding 10% NaOH and filtered, the filtrate is extracted with AcOEt, theorganic phase is dried over Na₂ SO₄ and the solvent is evaporated offunder vacuum. The residue is taken up with ether and the precipitateformed is drained. 0.54 g of the expected product is obtained, m.p.=190°C. (dec.).

NMR: 0.92:d:6H; 2.42:mt:1H; 3.65:s: 6H; 5.42:bs:2H; 6.3:dd:1H; 6.4:d:1H;6.6: d:2H; 6.67:s:1H; 6.85:d:1H; 7.3:t:1H.

PREPARATION 4.46

1- 4-3-(Diethylamino)propanoylamino!-2-iso-propylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazole-carboxylicacid.

(II: R₁ =4-NHCO(CH₂)₂ NEt₂ ; R₂ =2-iPr; R₃ =H; R₄ =Me).

A mixture of 0.22 g of 3-diethylaminopropanoic acid hydrochloride and 2ml of SOCl₂ in 2 ml of DCM is heated to reflux for 1 hour and thenconcentrated under vacuum. The acid chloride thereby obtained is usedwithout further treatment. Separately, a mixture of 0.47 g of thecompound obtained in Preparation 4.45 and 0.95 ml ofbis(trimethylsilyl)acetamide in 5 ml of acetonitrile is heated at 70° C.for 1 hour. After cooling to RT, the acid chloride prepared above, insolution in DCM, is added, followed by 0.17 ml of triethylamine, and themixture is left stirring for hour at RT. It is concentrated undervacuum, the residue is taken up with water, the pH is taken to 5 byadding 10% NaOH, the mixture is extracted with DCM, the organic phase isdried over Na₂ SO₄ and the solvent is evaporated off under vacuum. Theresidue is taken up with ether and the precipitate formed is drained.0.27 g of the expected product is obtained.

NMR (DMSO+TFA): 0.91:d:6H; 1.2:mt:6H; 2.55:mt:1H; 2.8:t:2H;3.1-3.22:u.c.:4H; 3.35:t:2H; 3.6:s:6H; 6.58:d:2H; 6.75:s: 1H;7.1-7.3:u.c.:2H; 7.4-7.55:u.c.:2H.

PREPARATION 4.47

1- 4-(3-Diethylaminopropyl)amino!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid.

(II: R₁ =4-NH(CH₂)₃ NEt₂ ; R₂ =2-iPr; R₃ =H; R₄ =Me).

A mixture of 0.55 g of the compound obtained in Preparation 3.59, 6.5 mlof acetic acid and 14 ml of 70% perchloric acid is heated to reflux for10 minutes. The reaction mixture is poured into water, the resultingmixture is taken to pH 5 by adding 10% NaOH and extracted with AcOEt,the organic phase is dried over Na₂ SO₄ and the solvent is evaporatedoff under vacuum. 0.5 g of the expected product is obtained.

NMR: 1.0:mt:6H; 1.25:t:6H; 1.9:mt: 2H; 2.55:s:1H; 3.0-3.3:u.c.:8H;3.7:s:6H; 5.9:s:1H; 6.3-6.55:u.c.:2H; 6.65:d:2H; 6.75 s:1H; 7.0:d:1H;7.3:t:1H.

PREPARATION 4.48

1- 4-N-Acetyl-N-(3-diethylaminopropyl)amino!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid.

(II: R₁ =4-N(COMe)(CH₂)₃ NEt₂ ; R₂ =2-iPr; R₃ =H; R₄ =Me).

0.38 g of the compound obtained in Preparation 4.47 and 0.36 ml ofbis(trimethylsilyl)acetamide in 10 ml of toluene is heated for 1 hour at60° C. 0.052 ml of acetyl chloride is added, followed by 0.1 ml oftriethylamine, and the mixture is left stirring for 2 hours at RT. It isconcentrated under vacuum, the residue is taken up with saturated NaClsolution, the mixture is extracted with AcOEt, the organic phase isdried over Na₂ SO₄ and the solvent is evaporated off under vacuum. 0.39g of the expected product is obtained.

NMR: 0.95:d:6H; 1.25:t:6H; 1.6-2.0: u.c.:5H; 2.65:sp:1H;3.0-3.3:u.c.:6H; 3.65: s:6H; 3.75:t:2H; 6.65:d:2H; 6.85:s:1H;7.2-7.6:u.c.:4H.

PREPARATION 4.49

1- 4- N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-5-2-(cyclopropylmethyloxy)-6-methoxyphenyl!-3-pyrazolecarboxylic acidpotassium salt. ##STR97##

A mixture of 3.8 g of the compound obtained in Preparation 3.61 and 0.92g of KOH in 76 ml of EtOH and 12 ml of water is left stirring for 20hours at RT. It is concentrated under vacuum, the residue is taken upwith toluene and the solvent is evaporated off under vacuum. 3.9 g ofthe expected product are obtained.

PREPARATION 4.50

1-(2-Methyl-4-nitrophenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylicacid.

(II':R'₁ =4-NO₂ ; R₂ =2-Me; R₃ =H; R₄ =Me).

A mixture of 3.5 g of the compound obtained in Preparation 3.56 and 0.44g of LiOH.H₂ O in 20 ml of MeOH and 4 ml of water is left stirringovernight. It is concentrated under vacuum, the residue is taken up withwater, the mixture is acidified to pH 3 by adding 10% HCl, and theprecipitate formed is drained and dried. 3.2 g of the expected productare obtained.

NMR: 2.9:s:3H; 3.58:s:6H; 6.6:d: 2H; 6.88:s:1H; 7.2-7.38:u.c.:2H;7.95:dd: 1H; 8.22:d:1H.

PREPARATION 4.51

1-(4-Amino-2-isobutylphenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylicacid.

(II':R'₁ =4-NH₂ ; R₂ =2-iBu; R₃ =H; R₄ =Me).

This compound is prepared according to the procedure described inPreparation 4.45, from 0.5 g of the compound obtained in Preparation3.62, 6 ml of acetic acid and 14 ml of 70% perchloric acid. 0.3 g of theexpected product is obtained.

NMR: 0.65:d:6H; 1.55:mt:1H; 1.9:d: 2H; 3.5:s:6H; 5.05:s:2H;6.0-7.3:u.c.:7H.

PREPARATION 4.52

1- 4-3-(Diethylamino)propanoylamino!-2-isobutyl-phenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid.

(II: R₁ =4-NHCO(CH₂)₂ NEt₂ ; R₂ =2-iBu; R₃ =H; R₄ =Me).

This compound is prepared according to the procedure described inPreparation 4.46, from 0.133 g of 3-diethylaminopropanoic acidhydrochloride and 1 ml of SOCl₂ in 1 ml of DCM and 0.29 g of thecompound obtained in Preparation 4.51 and 4 ml ofbis(trimethylsilyl)acetamide in 2 ml of acetonitrile. 0.15 g of theexpected product is obtained.

NMR: 0.7:d:6H; 1.1:t:6H; 1.65:mt: 1H; 2.0:d:2H; 2.75:t:2H; 3.1:qr:4H;3.3:t 2H; 3.6:s:6H; 6.5:d:2H; 6.7:s:1H; 7.1:d 1H; 7.2:t:1H;7.3-7.5:u.c.:2H; 10.3:s:1H; 15:s:1H.

PREPARATION 4.53

1-4-Amino-2-cyclopentylphenyl)-5-(2,6-dimethoxy-phenyl)-3-pyrazolecarboxylicacid. ##STR98##

This compound is prepared according to the procedure described inPreparation 4.45, from 0.9 g of the compound obtained in Preparation3.63, 11 ml of acetic acid and 27 ml of 70% perchloric acid. 0.52 g ofthe expected product is obtained.

NMR (DMSO+TFA): 1.18-1.9:u.c.:8H; 2.6: mt:1H; 3.6:s:6H; 6.6:d:2H;6.75:s:1H; 7.1-7.4:u.c.:4H.

PREPARATION 4.54

1- 4-3-(Diethylamino)propanoylamino!-2-cyclopentylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid. ##STR99##

This compound is prepared according to the procedure described inPreparation 4.46, from 0.22 g of 3-diethylaminopropanoic acidhydrochloride, 2 ml of SOCl₂ in 5 ml of DCM, 0.5=of the compoundobtained in Preparation 4.53 and 0.73 ml of bis(trimethylsilyl)acetamidein 2 ml of acetonitrile. 0.32=of the expected product is obtained.

NMR (DMSO+TFA): 1.1-1.8:u.c.:14H; 2.5: mt:1H; 2.72:t:2H; 3.02:u.c.:4H;3.22:mt: 2H; 3.58:s:6H; 6.5:d:2H; 6.65:s:1H; 7.03: d:1H; 7.2:t:1H;7.35:dd:1H; 7.5:d:1H.

PREPARATION 5.5

1- 4-N-(2-Diethylaminoethyl)carbamoyl!-3-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolecarboxylicacid potassium salt.

(II: R₁ =4-CONH(CH₂)₂ NEt₂ ; R₂ =3-iPr; R₃ =H; R₄ =Me).

0.34 g of the compound obtained in Preparation 3.65 and 0.073 g of KOHin 6 ml of dioxane and 2 ml of water is left stirring for 2 days at RT.It is concentrated under vacuum, the residue is taken up with tolueneand the mixture is concentrated under vacuum. 0.37 g of the expectedproduct is obtained, m.p. >260° C.

PREPARATION 4.56

5-(2,6-Dimethoxyphenyl)-1-(4-nitro-5,6,7,8-tetrahydro-1-naphthyl)-3-pyrazolecarboxylicacid.

(II':R'₁ =4-NO₂ ; R₂, R₃ =--(CH₂)₄ -; R₄ =Me).

A mixture of 4.2 g of the compound obtained in Preparation 3.66 isheated at 70° C. for 2 hours with 0.8 g of LiOH.H₂ O in 95 ml of EtOHand 5 ml of water. After cooling to RT, water is added, the mixture isacidified to pH 3 by adding 10% HCl, and the precipitate formed isdrained and dried. 4.16 g of the expected product are obtained,m.p.=130° C.

NMR: 1.7:mt:4H; 2.55:mt:2H; 2.82:mt: 2H; 3.65:s:6H; 6.65:d:2H;6.85:s:1H; 7.05 d:1H; 7.35:t:1H; 7.7:d:1H; 12.95:bs:1H.

PREPARATION 4.57

5-(2,6-Dimethoxyphenyl)-1-(5-(3-diethylamino-propanoylamino)-2-isopropylphenyl)-3-pyrazolecarboxylicacid.

(II: R₁ =5-NHCO(CH₂)₂ NEt₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃).

This compound is obtained from the methyl ester of Preparation 3.67.After recrystallization in methanol, m.p.=195-198° C.

NMR (DMSO+TFA): 0.65-1.35:u.c.:12H; 2.5 qt:1H; 2.82:t:2H; 3.15:mt:4H;3.36:t: 2H; 3.6:s:6H; 6.55:d:2H; 6.76:s:1H; 7.15-7.4:u.c.:3H; 7.8:d:1H.

EXAMPLE 1 2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-CONMe(CH₂)₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A) 1- 4-N-Methyl-N-(3-dimethylaminopropyl)-carbamoyl!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolylcarbonylchloride hydrochloride.

1.07 g of the acid obtained in Preparation 4.1 in 2 ml of thionylchloride is left stirring under nitrogen at RT for 5 hours. The mixtureis evaporated, and the residue is then taken up with DCM (3 times) toobtain the expected product, which is used in the next step withoutfurther treatment.

The acid chloride may also be prepared according to the procedure below:

A') 1- 4-N-Methyl-N-(3-dimethylaminopropyl)-carbamoyl!-2-isopropylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolylcarbonylchloride hydrochloride.

The potassium salt of Preparation 4.1a is redissolved in 130 ml ofethanol, 50 ml of ethanolic hydrogen chloride are added, the inorganicmatter is filtered off and the filtrate is evaporated under vacuum. Theresidue is redissolved in 100 ml of DCM, 11 ml of SOCl₂ are added slowlyand the mixture is heated to reflux for 4 hours. It is evaporated undervacuum, the residue is redissolved in 30 ml of DCM and the mixture isevaporated under vacuum; the operation is repeated 3 times.

B) 2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

A mixture containing 0.37 g of 2-amino-2-adamantanecarboxylic acid(compound B), 5 ml of acetonitrile and 0.82 ml ofbis(trimethylsilyl)acetamide is heated to reflux under nitrogen for 40minutes. After a return to RT, 0.3 ml of triethylamine and the productobtained in the preceding step, dissolved in 15 ml of acetonitrile, areadded. The mixture is left stirring at RT for 1 week and the solventsare concentrated. On adding ether, a crystallization is obtained. Thecrystals are stirred in a mixture of 1.5 ml of toluene and 1.5 ml ofacetonitrile. The insoluble matter is filtered off and rinsed and thesolvents are evaporated off. The residue is stirred in aqueous methanol,the mixture is then evaporated again and the residue is taken up withethenol. The mixture is extracted with DCM, and the organic phase iswashed with saturated NaCl solution and then chromatographed on silica,eluting with a DCM/MeOH/H₂ O (92:8:0.7; v/v/v) mixture. 0.18 g of theexpected product is obtained after trituration in ether, m.p.=185° C.(dec.).

NMR (DMSO+TFA): 0.95:d:6H; 1.6-2.2: u.c.:14H; 2.4-3:u.c.:12H; 3.1:mt:2H;3.5:mt: 2H; 3.65:s:6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.5:u.c.:4H.

Alternatively, step B may be performed in the following manner:

A mixture of 8.79 g of compound B and 22 ml ofbis(trimethylsilyl)acetamide in 120 ml of dry acetonitrile is heated toreflux under nitrogen for 40 minutes and cooled to RT. A solution of theacid chloride obtained according to A, starting from 23.83 g of the acidobtained in Preparation 4.1 and 140 ml of thionyl chloride, in 300 ml ofdry acetonitrile is then added. After stirring for 15 hours at RT andevaporation under vacuum, the residue is redissolved in 180 ml of MeOH,180 ml of water are added slowly, the mixture is stirred for one hour,the insoluble matter is filtered off and the filtrate is evaporatedunder vacuum after adding ethanol. After stirring in 200 ml of 1N HCl,the mixture is filtered, and the precipitate is washed with 1N HCl anddried under vacuum over P₂ O₅ to obtain 29.8 g of the product of EXAMPLE1, m.p.=211° C. (dec.) after recrystallization in 2-propanol.

EXAMPLE 1'

Internal salt of 2- 5-(2,6-dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-iso-propylphenyl!-3-pyrazolylcarbonylamino!-2-adamantane-carboxylicacid.

From the hydrochloride of the compound obtained in EXAMPLE 1, theinternal salt is liberated in the following manner:

0.97 g of the product of EXAMPLE 1 is dissolved in 10 ml of water andthe pH is raised to 7 by adding 1.3N sodium hydroxide. The product isfiltered off, washed with water and dried under vacuum over P₂ O₅ toobtain 0.86 g of internal salt, which is recrystallized in 3 ml ofacetonitrile to obtain 0.5 g of the expected internal salt.

NMR (DMSO+TFA): 1:mt:6H; 1.4-2.3:u.c. 14H; 2.3-3.4:u.c.:14H;3.5:u.c.:2H; 3.65:s 6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.5:u.c.:4H.

After recrystallization in 2-propanol, m.p.=238° C.

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2: u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H;3.1:mt 2H; 3.5:mt:2H; 3.6:s:6H; 6.6:d:2H; 6.75: s:1H; 7.1-7.5:u.c.:4H.

The product of EXAMPLE 1' may also be prepared without isolating theproduct of EXAMPLE 1, according to the following procedure:

A mixture of 9.7 g of compound B and 27 ml of bistrimethylsilylacetamidein 100 ml of anhydrous DCM is heated to reflux under nitrogen for 2hours. After cooling, the solution thereby obtained is poured into thesolution of the product of step A' of EXAMPLE 1 in 100 ml of DCM, andthe mixture is stirred overnight at RT. It is evaporated under vacuum,the residue is treated by stirring for 3 hours with 100 ml of MeOH and100 ml of water and the pH is raised to 7-7.5 by adding saturated NaHCO₃solution. After 1 hour of stirring, the mixture is filtered to obtain22.1 g of the expected product (HPLC purity 98.5%).

The internal salt may also be converted to its hydrochloride (product ofEXAMPLE 1) according to the following procedure:

6.85 g of internal salt in a mixture of 3.5 ml of concentrated HCl and40 ml of water are heated while stirring. After dissolution, the mixtureis allowed to cool with stirring, and the product is filtered off anddried under vacuum to obtain 6.5 g of hydrochloride.

From the internal salt, its hydrochloride may be obtained in thefollowing manner:

0.3 g of internal salt in 3 ml of MeOH and 2 ml of DCM are dissolvedwhile heating, the mixture is cooled to RT, 0.5 ml of 1.2N HCl is added,the mixture is concentrated under vacuum to 0.5 ml and cooled to -20° C.and the product is filtered off to obtain 0.2 g of the product ofEXAMPLE 1.

EXAMPLE 2

2-{1- 4-N-(2-Cyanoethyl)carbamoyl!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolylcarbonyl-amino)-2-adamantanecarboxylicacid.

(I: R₁ =4-CONHCH₂ CH₂ CN; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 2.6 g of the compound obtained in Preparation 4.2 and 20 mlof thionyl chloride is left stirring for 5 hours at RT. It isconcentrated under vacuum, the residue is taken up with DCM and thesolvent is evaporated off under vacuum. The acid chloride therebyobtained is used without further treatment. Separately, a mixture of1.09 g of 2-amino-2-adamantanecarboxylic acid and 4.2 ml ofbis(trimethylsilyl)acetamide in 20 ml of acetonitrile is heated toreflux under a nitrogen atmosphere for 30 minutes. After cooling, asolution of the acid chloride prepared above in 40 ml of acetonitrile isadded slowly, and the mixture is left stirring overnight at RT. It isconcentrated under vacuum, the residue is taken up with MeOH, a fewdrops of water are added and the mixture is left stirring for 2 hours atRT. The precipitate is drained, washed with MeOH and dried. Theprecipitate is chromatographed on silica H, eluting with a DCM/MeOH(100:3; v/v) mixture and then with a DCM/MeOH/AcOH (100:3:0.5; v/v/v)mixture. 1.96 g of the expected product are obtained aftercrystallization in ether, m.p.=269° C.

NMR: 1:d:6H; 1.4-2.1:u.c.:12H; 2.4-2.8 :u.c.:5H; 3.4:mt:2H; 3.5:s:6H;6.5:d:2H; 6.6:s:1H; 7.1-7.4:u.c.:2H; 7.5:d:1H; 7.8: s:1H; 8.9:t:1H.

EXAMPLE 3

2-{1- 4-N-(3-Aminopropyl)carbamoyl!-2-isopropyl-phenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolylcarbonyl-amino)-2-adamantanecarboxylicacid.

(I: R₁ =4-CONH(CH₂)₃ NH₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 0.3 g of the compound obtained in EXAMPLE 2 and 0.03 g ofRaney® nickel in 10 ml of MeOH is hydrogenated overnight at RT and atatmospheric pressure, the catalyst is filtered off and washed with MeOHand the filtrate is partially concentrated under vacuum. The crystalsformed are filtered off and washed with EtOH to obtain a first crop ofthe expected product. The filtrate is partially concentrated undervacuum and left stirring at RT. The crystals formed are drained andwashed with EtOH to obtain a second crop. By combining both crops, 0.045g of the expected product are obtained, m.p.=280° C. (dec.).

NMR: 1.1:d:6H; 1.5-2.2:u.c.:14H; 2.4-3 u.c.:5H; 3.3:mt:2H; 3.6:s:6H;6.6:d:2H; 6.7:s:1H; 7.2-7.4:u.c.:2H; 7.6:d:1H; 7.7: s:1H.

EXAMPLE 4

2-{1- 4-N-(2-Amidinoethyl)carbamoyl!-2-iso-propylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolyl-carbonylamino)-2-adamantanecarboxylicacid.

(I: R₁ =4-COHN(CH₂)₂ C(═NH)NH₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ;AA(OH)=2-carboxy-2-adamantyl)

Step A. A solution of 0.37 g of the compound obtained in EXAMPLE 2 in 10ml of EtOH and 10 ml of anhydrous ether is cooled in an ice bath, andHCl gas is then bubbled through it for 50 minutes. The mixture is leftfor 3 days at +5° C. and then concentrated under vacuum to obtain thehydrochloride of the intermediate imidate (R₁ =4-CONH(CH₂)₂ C(═NH)OEt).

Step B. The residue is taken up in 20 ml of anhydrous EtOH, the mixtureis cooled in an ice bath and ammonia is bubbled through it for 35minutes. The mixture is left stirring for 30 minutes at RT andconcentrated under vacuum, the residue is taken up in water andcrystallization is allowed to take place. After draining and then dryingthe crystals, the product is recrystallized in EtOH in the heated state.0.3 g of the expected product is obtained, m.p.=257° C. (dec. ).

NMR (DMSO+TFA): 1.1:d:6H; 1.5-2.2:u.c. :14H; 2.4-2.8:u.c.:3H;3.4-3.7:u.c.+s:8H; 6.6 d:2H; 6.7:s:1H; 7.2-7.4:u.c.:2H; 7.6:dd: 1H;7.8:bs:1H.

EXAMPLE 5

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-(2-dihydroimidazol-2-yl-ethyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid dihydrochloride. ##STR100## AA(OH)=2-carboxy-2-adamantyl)

A mixture containing 0.49 g of the intermediate imidate described inEXAMPLE 4, step A and 5 ml of 1,2-diaminoethane is stirred for 30minutes. The reaction medium is evaporated. On adding water, aprecipitate forms which is filtered off and then rinsed with water. Thisproduct is suspended in ethanol and ethereal hydrogen chloride is added.After evaporation of the solvent, the product is triturated in ether,filtered off, rinsed with ether and then dried at 60° C. over P₂ O₅. 0.3g of the expected product is obtained, m.p.=220° C. (dec.).

NMR: 1.05:d:6H; 1.5-2.2:u.c.:12H; 2.5 bs:2H; 2.6-2.8:u.c.:3H;3.55:mt:2H; 3.65: s:6H; 3.8:s:1H; 6.6:d:2H; 6.7:s:1H; 7.2-7.4:dd:1H;7.8:d:1H.

EXAMPLE 6

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-(3-(N',N'-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-CONH(CH₂)₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =Me;AA(OH)=2-carboxy-2-adamantyl).

A mixture is prepared containing 1.45 g of the compound of Preparation4.3, 30 ml of DCM, 0.38 ml of isobutyl chloroformate, 0.82 ml oftriethylamine and 17 ml of acetonitrile. The mixture is left stirring atRT for five and a half hours. Separately, 0.57 g of2-amino-2-adamantanecarboxylic acid, 10 ml of acetonitrile and 2.2 ml ofbis(trimethylsilyl)acetamide are mixed, and the mixture is heated toreflux under nitrogen for 30 minutes. After cooling, the mixed anhydrideformed above is added and the resulting mixture is left stirring at RTfor 1 day. The insoluble matter is filtered off and removed; thesolvents are evaporated off, water is then added, the mixture is stirredfor 30 minutes and the precipitate formed is filtered off. A secondfraction is obtained from the filtrate after adding ethanol, extractionwith DCM (twice), drying over MgSO₄ and evaporation of the solvents. The2 fractions combined are chromatographed on silica, eluting with aDCM/MeOH/H₂ O (90:10:0.8, then 88:12:1; v/v/v) mixture. 40 mg of theexpected product are obtained after trituration in isopropyl ether andfiltration, m.p.=220° C. (dec.).

NMR (DMSO+TFA): 1.1:d:6H; 1.5.2.2:u.c.:14H; 2.5:bs:2H; 2.75:s+mt:7H;3.1:u.c.:2H; 3.3:u.c.:2H; 3.65:s:6H; 6.6:d:2H; 6.7:s:1H;7.2-7.4:u.c.:2H; 7.6:dd:1H; 7.8:d:2H.

From the acids of formula (II) described in Table 4, and by workingaccording to the procedure described in EXAMPLE 1, the compoundsaccording to the invention of formula (I) described in Table 6 below areobtained.

                  TABLE 6                                                         ______________________________________                                         ##STR101##                                                                   EXAMPLE R.sub.1              M.p. °C. or NMR                           ______________________________________                                         7      CONH(CH.sub.2).sub.2 NMe.sub.2                                                                     210                                                                           NMR                                               8      CONH(CH.sub.2).sub.3 NEt.sub.2                                                                     185                                                                           NMR                                               9                                                                                     ##STR102##          205 NMR                                          10                                                                                     ##STR103##          240 NMR                                          11                                                                                     ##STR104##          >260 NMR                                         12 (a)                                                                                 ##STR105##          228 NMR                                          13 (a)                                                                                 ##STR106##          250 NMR                                          ______________________________________                                         (a) unsalified compounds.                                                

NMR:

EXAMPLE 7 (DMSO+TFA): 1.1:d:6H; 1.5-2.2u.c.:12H; 2.4-2.8:u.c.:3H;2.8:s:6H; 3.25:mt:2H; 3.5-3.7:u.c.:8H; 6.6:d:2H; 6.7:s:1H;7.2-7.5:u.c.:2H; 7.7:dd:1H; 7.9:d:1H.

EXAMPLE 8: 0.8-1.2:u.c.:12H; 1.4-2.2: u.c.:14H; 2.45:bs:2H; 2.6.:mt:1H;2.8:mt:6H; 3.3:mt:2H; 3.5:s:6H; 6.5:d:2H; 6.65:s:1H; 7.1-7.4:u.c.:3H;7.6:dd:1H; 7.8:bs:1H; 8.7:t:1H.

EXAMPLE 9 (DMSO+TFA ):0.8-1.3:u.c.:8H; 1.6-2.2:u.c.:14H;2.3-2.8:u.c.:3H; 3:mt:2H; 3.2-3.8:u.c.:12H; 6.6:d:2H; 6.7:s:1H;7.2-7.4:u.c.:2H; 7.65:d:1H; 7.9:bs:1H.

EXAMPLE 10: 1.05:d:6H; 1.6-2.2:u.c.: 12H; 2.5:bs:2H; 2.7:mt:1H;3.6:s:6H; 6.6:d:2H; 6.7:s:1H; 7.05-7.25:u.c.:4H; 7.8-8.2:s:1H; 11:s:1H.

EXAMPLE 11 (DMSO+TFA): 1.1-1.3:u.c.:12H; 1.6-2.2:u.c.:12H; 2.6:bs:2H;2.7:mt:1H; 2.9:s:6H; 3.05:bs:2H; 3.3:bs:2H; 3.7:s:6H; 6.65:d:2H;6.75:s:1H; 7.25-7.45:u.c.:3H; 7.75:d:1H; 7.95:bs:1H.

EXAMPLE 12: 1:d:6H; 1.3-2.1:u.c.:16H; 2.6:mt:1H; 2.75:mt:2H;3.1-3.8:u.c.:5H; 3.4 :s:2H; 3.6:s:6H; 6.5:d:2H; 6.6:s:1H;7.1-7.3:u.c.:8H; 7.5:d:1H; 7.7:s:1H; 8.2: d:1H.

EXAMPLE 13 (DMSO+TFA): 1.05:d:6H; 1.3-2.3 :u.c.:17H; 2.3-2.6:u.c.:2H;2.65:mt:1H; 2.9-3.7:u.c.+s:12H; 4.2:u.c.:1H; 6.4:u.c.:2H; 6.7:bs:1H;7.0-7.3:u.c.:2H; 7.4-7.6:u.c.:1H; 7.7:bs:1H.

EXAMPLE 14

2- 5-(2,6-Dimethoxyphenyl)-1- 4- N-methyl-N-(3-N',N'-dimethylamino)propyl)aminosulphonyl!-2-isopropyl-phenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-SO₂ NMe(CH₂)₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ;AA(OH)=2-carboxy-2-adamantyl).

850 mg of the acid obtained in Preparation 4.11 and 3 ml of thionylchloride are left stirring at RT for five and a half hours. 10 ml oftoluene are added and the reaction medium is then evaporated undervacuum (twice). 1 g of chloride of the acid obtained in Preparation 4.11is thereby obtained. A mixture containing 0.41 g of2-amino-2-adamantanecarboxylic acid and 3.5 ml ofbis(trimethylsilyl)acetamide in 5 ml of acetonitrile is left stirringfor four and a half hours. A solution of the acid chloride preparedabove in 5 ml of acetonitrile and 1 ml of triethylamine is added to thisreaction medium, and the mixture is left stirring for 4 days at RT. 3 mlof water and 5 ml of methanol are added, the mixture is left stirringfor 4 hours at RT and then filtered and the filtrate is evaporated undervacuum. The residue is triturated in 6 ml of 1N HCl, ethanol is thenadded and the mixture is evaporated under vacuum. The residue is stirredwith 200 ml of DCM and 5 ml of water, settling is allowed to take place,and the organic phase is separated, dried over Na₂ SO₄ and evaporatedunder vacuum to obtain 1.26 g of crude product. The latter isrecrystallized in 5 ml of MeCN, the solution is cooled to -20° C. and0.6 g of expected product is filtered off, m.p.=211° C.

NMR: 1:d:6H; 1.4-2.1:u.c.:14H; 2.4-2.5:mt:2H; 2.5-2.65:mt:1H; 2.6:s:3H;2.65:s:6H; 2.9:mt:4H; 3.5:s:6H; 6.5:d:2H; 6.7:s:1H; 7.15-7.4:u.c.:3H;7.45-7.6:u.c.:2H.

EXAMPLE 15

2-{5-(2,6-Dimethoxyphenyl)-1- 4- N-3-(N',N'-dimethylamino)propyl!carbamoyl!-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino}-2-adamantanecarboxylicacid.

(I: R₁ =4-CONH(CH₂)₃ NMe₂ ; R₂, R₃ =--(CH₂)₄ -; R₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

0.47 g of the compound obtained in Preparation 4.12 in solution in 5 mlof SOCl₂ and 30 ml of DCM is heated for one and a half hours at 40° C.The mixture is evaporated under vacuum to obtain the acid chloride,which is redissolved in 5 ml of acetonitrile and added to the solutionobtained by refluxing for 2 hours a mixture of 0.28 g of compound B,0.69 ml of bis(trimethylsilyl)acetamide and 3 ml of acetonitrile. 0.26ml of triethylamine is added and the mixture is left stirring for 2hours at RT. It is evaporated under vacuum, the residue is triturated in2 ml of saturated NaCl solution, and the product is filtered and driedunder vacuum to obtain 0.77 g. The product is chromatographed on silicaH, eluting with a DCM/MeOH/water (80:20:2.5; v/v/v) mixture. The eluateis evaporated, and the residue is triturated in ether and filtered offto obtain 0.11 g of expected product, m.p.=200° C. (gum).

NMR: 1.4-2.05:u.c.:18H; 2.1:s:6H; 2.2: t:3H; 2.4-2.8:u.c.:6H; 3.2:qr:2H;3.6:s: 6H; 6.6:d:2H; 6.65:s:1H; 6.8-7:dd:2H; 7.2-7.3:u.c.:2H; 8.2:t:1H.

EXAMPLE 16

2-{5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(2-(N',N'-dimethylamino)ethyl)aminosulphonyl!-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino}-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-SO₂ NMe(CH₂)₂ NMe₂ ; R₂, R₃ =--(CH₂)₄ -; R₄ =CH₃ ;AA(OH)=2-carboxy-2-adamantyl).

0.5 g of the salt obtained in Preparation 4.13 in 10 ml of SOCl₂ is leftstirring for 15 hours at RT, and the mixture is then evaporated withtoluene to obtain the acid chloride, into which a solution of thesilylated compound B, obtained by stirring a mixture of 0.279 g ofcompound B, 2 ml of bis(trimethylsilyl)acetamide and 8 ml ofacetonitrile for 6 hours at RT, is poured. After stirring for 20 days atRT, the mixture is evaporated under vacuum, and the residue is thenstirred for 1 hour at RT with 5 ml of water and 5 ml of methanol; themixture is filtered and the filtrate is evaporated under vacuum and thenchromatographed on silica H, eluting with a DCM/MeOH/AcOH mixture. Theresidue is triturated in ether and filtered off to obtain 0.31 g of theexpected product, m.p.>260° C.

NMR (DMSO+TFA): 1.6-2.3:u.c.:16H; 2.6: u.c.:2H; 2.9:bs:9H; 3.1:mt:2H;3.4:mt:2H; 3.6:mt:2H; 3.7:s:6H; 6.7:d:2H; 6.85:s: 1H; 7.15:d:1H;7.4:t:1H; 7.5:bs:1H; 7.6:d :1H.

EXAMPLE 17

2-5-(2,6-Dimethoxyphenyl)-1-(2-methyl-4-carbamoylphenyl)-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CONH₂ ; R₂ =2-CH₃ ; R₃ =H; R₄ =CH₃ ;AA(OH)=2-carboxy-2-adamantyl).

A suspension of 220 mg of compound B and 0.4 mg ofbis(trimethylsilyl)acetamide in 10 ml of acetonitrile is heated toreflux for 1 hour.

Separately, a solution is prepared containing 330 mg of the compoundobtained in Preparation 4.14 and 0.15 ml of triethylamine in 10 ml ofacetonitrile and is cooled to -5° C., 0.13 ml of isobutyl chloroformateis added, the mixture is left stirring for 1 hour at RT, and the mixedanhydride obtained is added to the solution of the silylated compound Bprepared above. The mixture is left for 8 days at RT, the insolublematter is then filtered off, the filtrate is evaporated to dryness andthe residue is then dissolved in 5 ml of DCM. The mixture is washed with1.2N HCl solution, dried over Na₂ SO₄ and evaporated; 5 ml of DCM areadded, and the precipitate formed is filtered off and then dissolved in1 ml of MeOH. The crystals formed are filtered off to obtain 100 mg ofthe expected product, m.p.=290° C. (dec.).

NMR: 1.4-2.3:u.c.:15H; 2.55:u.c.:2H; 3.6:s:6H; 6.6:d:2H; 6.7:s:1H;7.05:d: 1H; 7.3:t:1H; 7.4:s:2H; 7.6:dd:1H; 7.75:s 1H; 7.9:s:1H.

EXAMPLE 18

2-{5-(2,6-Dimethoxyphenyl)-1- 2,3-dimethyl-4-N-(2-(N',N'-dimethylamino)ethyl)carbamoyl!phenyl!-3-pyrazolylcarbonylamino}-2-adamantanecarboxylicacid.

(I: R₁ =4-CONH(CH₂)₂ NMe₂ ; R₂ =2-CH₃ ; R₃ CH₃ ; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A solution of 1.3 g of the product of Preparation 4.15 in 10 ml of SOCl₂and 50 ml of DCM is heated to reflux for one and a half hours. It isevaporated under vacuum to obtain the acid chloride, which isredissolved in 10 ml of acetonitrile and added to the solution obtainedafter 2 hours of heating to reflux a mixture of 0.82 g of compound B and2 ml of bis(trimethylsilyl)acetamide in 10 ml of acetonitrile. 0.77 mlof triethylamine is added and the mixture is left stirring for 15 hoursat RT. After evaporation under vacuum, trituration in 10 ml of saturatedNaCl solution, filtration and drying under vacuum, the product ischromatographed on silica H, eluting with a DCM/MeOH/water (100:10:1;v/v/v) mixture. After evaporation of the solvents and trituration inether, the residue is filtered off to obtain 0.7 g of expected product,m.p.=210° C.

NMR: 1.6-2.2:u.c.:12H; 2:s:3H; 2.25: s:3H; 2.35:s:6H;2.5-2.7:u.c.:2H+2H; 3.4:qr :2H; 3.7:s:6H; 6.65:d:2H; 6.8:s:1H;7.0-7.2:u.c.:2H; 7.3-7.45:u.c.:2H; 8.4:t:1H.

EXAMPLE 19

2-{5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(2-(N',N'-diethylamino)ethyl)carbamoyl!-2-methoxyphenyl!-3-pyrazolylcarbonylamino}-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-CONMe(CH₂)₂ NEt₂ ; R₂ =2-OCH₃ ; R₃ =H; R₄ =CH₃ ;AA(OH)=2-carboxy-2-adamantyl).

1.2 g of the product of Preparation 4.16 in 12 ml of SOCl₂ and 12 ml ofDCM are left stirring for 24 hours at RT. After evaporation under vacuumfollowed by 2 azeotropic evaporations with 30 ml of toluene, the acidchloride obtained is redissolved in 10 ml of acetonitrile and added tothe solution obtained by refluxing a mixture of 0.43 g of compound B and1.1 ml of bis(trimethylsilyl)acetamide in 20 ml of acetonitrile for 1hour 15 minutes. The resulting mixture is left stirring under reflux for4 hours and evaporated under vacuum, and the residue is stirred in 4 mlof MeOH and 0.5 ml of H₂ O; the mixture is evaporated under vacuum andthe residue is then chromatographed on silica H, eluting withDCM/MeOH/20% NH₄ OH (95:5:0.5; 90:10:0.5; 85:15:0.5; v/v/v) mixtures toobtain 0.3 g of expected product, m.p.=170° C. (dec.).

NMR: 0.8:mt:3H; 1:mt:3H; 1.5-3.6:mt: 34H; 6.5:d:2H; 6.65:s:1H;6.95:mt:2H; 7.3 :mt:3H.

EXAMPLE 20

2-{5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(2-(N',N'-diethylaminoethyl)carbamoyl!-2-chlorophenyl!-3-pyrazolylcarbonylamino}-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-CONMe(CH₂)₂ NEt₂ ; R₂ =2-Cl; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl.

1.3 g of the product of Preparation 4.17 in 12 ml of DCM and 12 ml ofSOCl₂ are left stirring for 24 hours at RT. After evaporation undervacuum followed by 2 azeotropic evaporations with 30 ml of toluene, theacid chloride obtained is redissolved in 10 ml of acetonitrile and addedto the solution obtained by refluxing a mixture of 0.46 g of compound Band 1.2 ml of bis(trimethylsilyl)acetamide in 20 ml of acetonitrile for1 hour 15 minutes. The resulting mixture is left stirring under refluxfor 4 hours and then evaporated under vacuum, the residue is trituratedin 4 ml of MeOH and 2 ml of water, and the mixture is stirred for 30minutes at RT and evaporated under vacuum. The residue ischromatographed on silica H, eluting with a DCM/MeOH/20% NH₄ OH(80:20:0.5; v/v/v) mixture to obtain 0.3 g of expected product; m.p.160° C. (dec.).

EXAMPLE 21

2-{5-(2,6-Dimethoxyphenyl)-1- 4-N-(2-morpholinoethyl)carbamoyl!-2-chlorophenyl!-3-pyrazolylcarbonyl-amino}-2-adamantanecarboxylicacid hydrochloride. ##STR107## AA(OH)=₂ -carboxy-2-adamantyl).

A mixture of 1.4 g of the product of Preparation 4.18, 14 ml of SOCl₂and 80 ml of DCM is left stirring for 18 hours at RT. After evaporationunder vacuum followed by 2 azeotropic evaporations with 30 ml of tolueneand redissolution of the acid chloride formed in 20 ml of acetonitrile,the solution is added to the solution obtained by refluxing a suspensionof 0.53 g of compound B in 1.33 ml of bis(trimethylsilyl)acetamide and30 ml of acetonitrile for 4 hours. After stirring under reflux for 4hours, the mixture is evaporated under vacuum, the residue is stirredwith 10 ml of MeOH and 1 ml of water and the mixture is filtered. Afterstirring the precipitate for 1 hour with 5 ml of H₂ O and 5 drops ofconcentrated HCl, filtration and washing with 1 ml of H₂ O, 5 ml ofpentane and 5 ml of isopropyl ether, 0.7 g of expected product isobtained, m.p.=200° C.

NMR: 1.5-2.2:u.c.:12; 2.6:bs:2; 2.85: bs:4; 3.3-3.8:mt:20; 6.6:d:2H;6.75:s:1H; 7.3:t:1H; 7.45:mt:2H; 7.8:dd:1H; 7.95:d: 1H; 8.85:bs:1H.

EXAMPLE 22

2-5-(2,6-Dimethoxyphenyl)-1-(3-chloro-4-cyano-phenyl)-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CN; R₂ =3-Cl; R₃ =H; R₄ =CH₃ ; AA(OH)=2-carboxy-2-adamantyl).

A mixture containing 0.36 g of the compound obtained in Preparation4.19, 0,145 ml of isobutyl chloroformate and 0.145 ml of triethylaminein 5 ml of DCM is left stirring at RT for 3 days. Separately, a mixturecontaining 0.23 g of compound B and 0.34 ml ofbis(trifluoromethyl)acetamide in 2 ml of acetonitrile is brought toreflux for 1 hour. The 2 solutions thus prepared are mixed and theresulting mixture is left stirring at RT for 48 hours. After filtrationand washing with methanol, the solvents are evaporated off and theresidue is then chromatographed on silica, eluting with a DCM/MeOH/AcOH(100:1:0.5; v/v/v) mixture to obtain 120 mg of the expected product,m.p.=292° C.

EXAMPLE 23

2-5-(2,6-Dimethoxyphenyl)-1-(4-carbamoyl-3-chlorophenyl)-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CONH₂ ; R₂ =3-Cl; R₃ =H; R₄ =CH₃ ;AA(OH)=2-carboxy-2-adamantyl).

A mixture containing 0.73 g of the compound obtained in Preparation4.20, 0.263 ml of isobutyl chloroformate and 0.26 ml of triethylamine in5 ml of DCM is left stirring at RT for 24 hours.

Separately, a mixture containing 0.34 g of compound B and 0.65 ml ofbis(trimethylsilyl)acetamide in 2 ml of acetonitrile is brought toreflux for 1 hour. The 2 solutions thus prepared are mixed and theresulting mixture is left stirring at RT for 4 days. After filtration,washing with 1N HCl and then EtOH and drying over MgSO₄, the residue ischromatographed on silica H, eluting with a DCM/MeOH/AcOH (100:2:1;v/v/v) mixture, m.p.=293° C.

EXAMPLE 24

2-{1- 4-N-Methyl-N-(2-(N',N'-dimethylamino)-ethyl)carbamoyl!-2-cyclopropylphenyl!-5-(2,6-dimethoxy-phenyl)-3-pyrazolylcarbonylamino}-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-CONMe(CH₂)₂ NEt₂ ; R₂ =2-cyclopropyl; R₃ =H; R₄ =CH₃ ;AA(OH)=2-carboxy-2-adamantyl).

0.5 g of the product of Preparation 4.21 in 5 ml of DCM and 1 ml ofSOCl₂ is left stirring for 24 hours at RT. After evaporation undervacuum followed by 2 azeotropic distillations with 30 ml of toluene, theacid chloride formed is redissolved in 5 ml of acetonitrile and added tothe solution obtained by refluxing a suspension of 0.19 g of compound Bin 0.5 ml of bis(trimethylsilyl)acetamide and 8.5 ml of acetonitrile fortwo and a half hours, and the mixture is stirred for 12 hours at RT. Itis evaporated under vacuum, the residue is stirred for 45 minutes with3.5 ml of MeOH and 1 ml of H₂ O, 2.5 ml of H₂ O are then added dropwiseand the mixture is filtered. After evaporation of the filtrate undervacuum and drying under vacuum for 24 hours at 60° C., 0.14 g ofexpected product are obtained, m.p.=135° C. (dec.).

NMR (DMSO+TFA): 0.6:u.c.:2H; 0.9:u.c.:2H; 1.2:u.c.:6H; 1.5-2.2:u.c.:12H;2.6:u.c.:2H; 2.9:bs:3H; 3.2:u.c.:6H; 3.6:s:6H; 3.7:u.c.:2H; 6.6:d:2H;6.75:s:1H; 6.85:s:1H; 7.1-7.4:u.c.:3H.

EXAMPLE 25

2-{1- 3-N-Methyl-N-(2-(N',N'-dimethylamino)-ethyl)carbamoyl!-4-chlorophenyl!-5-(2,6-dimethoxy-phenyl)-3-pyrazolylcarbonylamino}-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =3-CONMe(CH₂)₂ NMe₂ ; R₂ =4-Cl; R₃ =H; R₄ =CH₃ ;AA(OH)=2-carboxy-2-adamantyl).

A solution of 0.43 g of the product of Preparation 4.22 in 10 ml of DCMand 6 ml of SOCl₂ is left stirring for 15 hours at RT. After evaporationunder vacuum followed by 2 azeotropic distillations with 30 ml oftoluene, the acid chloride is redissolved in 3 ml of acetonitrile, andthe solution is added to the solution obtained by refluxing a suspensionof 0.17 of compound B in 0.5 ml of bis(trimethylsilyl)acetamide and 10ml of acetonitrile for 3 hours. The mixture is stirred under reflux for3 hours and then for 15 hours at RT. It is evaporated under vacuum, andthe residue is stirred for 1 hour with 12 ml of MeOH and 6 ml of water.The MeOH is evaporated off under vacuum, the residue is extracted twicewith 50 ml of DCM and the organic phase is dried over Na₂ SO₄ andevaporated under vacuum to obtain 0.16 g of expected product, m.p. 206°C. (dec.).

NMR: 1.5-2.3:u.c.:12H; 2.6-3.8:u.c.: 21H; 6.7:d:2H; 6.8:s:1H;7.1-7.7:u.c.:4H.

EXAMPLE 26

2-{1- 5-N-Methyl-N-(3-(N',N'-dimethylamino)-propyl)carbamoyl!-2-methylphenyl!-5-(2,6-dimethoxyphenyl)-3-pyrazolylcarbonylamino}-2-adamantanecarboxylicacid.

(I: R₁ =5-CONMe(CH₂)₃ NMe₂ ; R₂ =2-CH₃ ; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A solution of 1.7 g of the product of Preparation 4.23 in 15 ml of SOCl₂is left stirring for five and a half hours at RT. After evaporationunder vacuum followed by 3 azeotropic distillations with 30 ml of DCM,the acid chloride formed is redissolved in 30 ml of acetonitrile, andthe solution is added to the solution obtained by refluxing a suspensionof 0.69 g of compound B in 1.75 ml of bis(trimethylsilyl)-acetamide and6 ml of acetonitrile for 1 hour. After stirring for 15 hours at RT andevaporation under vacuum, the residue is dissolved in 13 ml of MeOH, 12ml of water are added slowly and the mixture is stirred for 30 minutesat RT. After evaporation under vacuum, trituration of the residue in 5ml of 1N HCl, decantation, 3 extractions of the residual gum with 100 mlof DCM and drying over MgSO₄, the organic phase is evaporated and theresidue is then dissolved in 15 ml of water. The mixture is alkalinizedwith 30% NaOH to pH 8 and crystallization is then inducedultrasonically. After filtration, the residue is recrystallized intoluene and dried under vacuum at 60° C. to obtain 1.32 g of expectedproduct, m.p.=165° C.

NMR (DMSO+TFA): 1.6-2.2:u.c.:14H; 2.2: s:3H; 2.5-3.2:u.c.:13H;3.5:mt:2H; 3.7:s: 6H; 6.65:d:2H; 6.8:s:1H; 7.3-7.6:u.c.:3H.

From the acids II described in Table 5 or in the Preparations, byfollowing the procedures indicated above, the compounds according to theinvention collated in Table 7 below are prepared.

                  TABLE 7                                                         ______________________________________                                         ##STR108##                                                                                                         M.p. °C.                         EXAMPLE                               or                                      (from)  R.sub.1          R.sub.2 R.sub.3                                                                            NMR                                     ______________________________________                                        27 (4.24)                                                                             4-CONMe(CH.sub.2).sub.2 NMe.sub.2                                                              2-OCH.sub.3                                                                           H    195                                                                           (dec.)                                  28 (4.25)                                                                              ##STR109##      2-OCH.sub.3                                                                           H    200 (dec.) NMR                          29 (4.26)                                                                             4-SO.sub.2 NMe(CH.sub.2).sub.3 NMe.sub.2                                                       2-CH.sub.3                                                                            3-   266                                                                      CH.sub.3                                                                           (dec.)                                                                        NMR                                     30 (4.27)                                                                             5-CONMe(CH.sub.2).sub.2 NMe.sub.2                                                              2-Cl    H    198                                                                           (dec.)                                                                        NMR                                     31 (4.28)                                                                             4-CONMe(CH.sub.2).sub.2 NEt.sub.2                                                              2-CF.sub.3                                                                            H    180                                                                           (dec.)                                                                        NMR                                     32 (4.29)                                                                             5-CONMe(CH.sub.2).sub.2 NMe.sub.2                                                              2-OCH.sub.3                                                                           H    208                                                                           NMR                                     33 (4.31) (a)                                                                         4-CONH(CH.sub.2).sub.3 N(nBu).sub.2                                                            2-iPr   H    165                                     34 (4.40) (a)                                                                         4-CONEt(CH.sub.2).sub.2 NEt.sub.2                                                              2-iPr   H    230                                                                           NMR                                     35 (4.33)                                                                              ##STR110##      2-iPr   H    253 (dec.)                              36 (4.39)                                                                              ##STR111##      2-iPr   H    167                                     ______________________________________                                         (a) unsalified compound.                                                 

NMR:

EXAMPLE 28: 1.3-3.7:mt:26H; 6.55:d:2H; 6.65:s:1H; 6.9:mt:3H;7.15-7.5:mt:4H.

EXAMPLE 29: 1.5-2.3:u.c.:17H; 2.55:s:2H; 2.8:s:9H; 2.95-3.3:u.c.:4H;3.6:s:6H; 6.6:d:2H; 6.7:s:1H; 7-7.7:u.c.:3H.

EXAMPLE 30: 1.4-2.3:u.c.:12H; 2.6:bs:2H; 2.7:bs:3H; 2.8:bs:6H;3.4:u.c.:2H; 3.6:s:6H; 3.8:u.c.:2H; 6.6:d:2H; 6.82:s:1H;7.2-7.8:u.c.:5H; 13.0:bs:1H.

EXAMPLE 31 (DMSO+TFA): 1.2:t:6H; 1.5-2.2:u.c.:12H; 2.5:bs:2H; 2.9:s:3H;3.1-3.5:u.c.:9H; 3.6:s:6H; 3.8:u.c.:2H; 6.6:d:2H; 6.8:s:1H; 7.3:u.c.:3H;7.7:d:1H; 8:s:1H.

EXAMPLE 32: 1.6-2.2:u.c.:12H; 2.45:s:6H; 2.60:bs:2H; 2.85:s:3H;3.40:u.c.:2H; 3.56:s:3H; 3.60:s:6H; 3.70:u.c.:2H; 6.60:d:2H; 6.78:s:1H;7.00:t:1H; 7.20:u.c.:3H; 7.40:bs:1H.

EXAMPLE 34 (DMSO+TFA): 0.9-1.3:u.c.:15H; 1.6-2.2:u.c.:8H; 2.7:u.c.:1H;3.1-3.4:u.c.:8H; 3.6-3.8:u.c.:8H; 6.55:d:2H; 6.75:s:1H; 7.1-7.4:u.c.:4H.

EXAMPLE 37

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrogen sulphate.

0.5 g of the compound obtained in EXAMPLE 1' is added to a solution of0.08 g of H₂ SO₄ in 5 ml of MeOH, this solution is poured into 150 ml ofether cooled to 5° C., and the precipitate formed is drained. 0.54 g ofthe expected product is obtained. After recrystallization in water,m.p.=212° C. (dec.). After recrystallization in 2-isopropanol, m.p.=263°C.

NMR (DMSO+TFA): 1.1:d:6H; 1.5-2.2:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H;3.1:mt:2H; 3.5:mt:2H; 3.65:s:6H; 6.6:d:2H; 6.75:s:1H; 7.1-7.5:u.c.:4H.

The product of EXAMPLE 37 may also be prepared according to theprocedure below:

22 ml of concentrated H₂ SO₄ are added slowly and with stirring to asuspension of 3.4 g of internal salt of EXAMPLE 1' in 34 ml of water,and the mixture is heated to 40' until a change is obtained in theappearance of the suspension. The latter is allowed to cool to RT for 4hours with stirring, and the product is filtered off and dried to obtain3.8 g of expected hydrogen sulphate.

EXAMPLE 38

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid benzenesulphonate.

A mixture of 0.5 g of the compound obtained in EXAMPLE 1' and 0.16 g ofbenzenesulphonic acid in 5 ml of MeOH is poured into 75 ml of ethercooled to 5° C., and the precipitate formed is drained. 0.06 g of theexpected product is obtained, m.p.=170° C. (dec.).

NMR (DMSO+TFA): 1:d:6H; 1.4-2.2:u.c.:14H; 2.45:bs:2H; 2.5-3.2:u.c.:12H;3.4:mt:2H; 3.55:s:6H; 6.5:d:2H; 6.65:s:1H; 7-7.4:u.c.:7H; 7.5:mt:2H.

EXAMPLE 39

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid citrate.

0.084 g of citric acid is added at RT to a solution of 0.3 g of thecompound obtained in EXAMPLE 1' in 5 ml of EtOH and 3 ml of DCM, and themixture is left stirring for 2 hours at RT. It is concentrated undervacuum and the residue is recrystallized in 2-propanol. 0.26 g of theexpected product is obtained, m.p.=168° C.

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.3:u.c.:14H; 2.5:bs:2H;2.6-3.3:u.c.:16H; 3.3-3.8:s+u.c.:8H; 6.6:d:2H; 6.75:s:1H;7.1-7.5:u.c.:4H.

EXAMPLE 40

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid maleate.

0.1 g of the compound obtained in EXAMPLE 1' and 0.017 g of maleic acidare dissolved in the heated state in 2.3 ml of 2-propanol, and themixture is concentrated under vacuum. The residue is dissolved in 0.3 mlof EtOH, this solution is poured into 30 ml of ether and the precipitateformed is drained. 0.04 g of the expected product is obtained, m.p.=260°C. (dec.).

NMR (DMSO+TFA): 1.05:d:6H; 1.55-2.2:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H;3.5:mt:2H; 3.65:s:6H; 6.3:s:2H; 6.6:d:2H; 6.75:s:1H; 7.15-7.45:u.c.:4H.

EXAMPLE 41

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid (S)-(+)-arginine salt.

0.1 g of the compound obtained in EXAMPLE 1' and 0.03 g of(S)-(+)-arginine are dissolved in the heated state in 4 ml of MeOH, andthis solution is concentrated to 1 ml and poured into 10 ml of ethercooled to 5° C. 0.055 g of the expected product is obtained afterdraining and drying over P₂ O₅, m.p.=176° C. (dec.).

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:20H; 2.55:bs:2H;2.6-3.55:u.c.:16H; 3.65:s:6H; 3.95:t:1H; 6.6:d:2H; 6.75:s:1H;7.15-7.4:u.c.:4H.

EXAMPLE 42

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid edisylate.

A) 1,2-Ethanedisulphonic acid.

A solution of 3 g of 1,2-ethanedisulphonic acid disodium salt in 10 mlof water is introduced slowly into 200 ml of Dowex® 50 W×8 resin, andthe product is eluted with 200 ml of demineralized water. The eluate isdiluted by adding EtOH and concentrated under vacuum. 3.35 g of theexpected product are obtained in the form of an oil which crystallizesat RT.

B) 2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid edisylate.

0.05 g of the compound obtained in EXAMPLE 1' and 0.04 g of the compoundobtained in step A are dissolved in the heated state in 2 ml of2-propanol, and the mixture is concentrated under vacuum. The residue isdissolved in 0.3 ml of water and 8 drops of dioxane, and crystallizationis allowed to take place at RT. The crystallized product formed isdrained, washed with water and dried at 90° C. under vacuum. 0.042 g ofexpected product is obtained, m.p.=266° C. (dec.).

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:14H; 2.5:bs:2H;2.6-3:u.c.+s:14H; 3.1:mt:2H; 3.5:mt:2H; 3.65:s:6H; 6.6:d:2H; 6.75:s:1H;7.15-7.45:u.c.:4H.

EXAMPLE 43

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid sodium salt.

0.206 g of the compound obtained in EXAMPLE 1' and 0.026 g of sodiummethylate are dissolved in 1 ml of MeOH and a few drops of DCM, and thissolution is then poured into 50 ml of ether cooled to 5° C. Thegelatinous precipitate formed is drained and dried over P₂ O₅ and undervacuum. 0.15 g of the expected product is obtained, m.p.=191° C.

This compound may also be obtained by following the procedure describedbelow.

0.7 ml of a solution of 0.104 g of NaOH in 10 ml of MeOH is added to asolution of 0.1 g of the compound obtained in EXAMPLE 1' in 5 ml of MeOHand 4 ml of DCM, and the mixture is concentrated under vacuum. Theresidue is dissolved in 1 ml of 2-propanol, this solution is poured into75 ml of ether cooled to 5° C. and the precipitate formed is drained.0.005 g of the expected product is obtained.

NMR: 1:d:6H; 1.4-2.3:u.c.:20H; 2.55:bs:2H; 2.6:mt:1H; 2.85:d:3H; 3.1 and3.4:2mt:4H; 3.6:s:6H; 6.55:s:1H; 6.6:s:2H; 6.95:s:1H; 7-7.35:u.c.:4H.

The NMR spectrum recorded in the presence of DMSO+TFA is slightlydifferent.

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.3:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H;3.1:mt: 2H; 3.5:mt:6H; 6.6:d:2H; 6.75:s:1H; 7.1-7.4:u.c.:4H.

EXAMPLE 44

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid fumarate.

0.1 g of the compound obtained in EXAMPLE 1' and 0.017 g of fumaric acidare dissolved in 1.5 ml of EtOH, 1.5 ml of DCM and 4 ml of MeOH, and themixture is left stirring for 10 minutes at RT. It is partiallyconcentrated under vacuum and crystallization is allowed to take place.0.025 g of the expected product is obtained after draining and washingwith EtOH, m.p.=243° C.

NMR (DMSO+TFA): 1:d:6H; 1.5-2.3:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:1ON;3.1:mt:2H; 3.4:mt:2H; 3.6:s:6H; 6.5-6.7:d+s:3H; 6.75:s:1H;7.1-7.4:u.c.:5H.

EXAMPLE 45

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid N-methyl-D-glucamine salt.

A solution of 0.07 g of the compound obtained in EXAMPLE 1' in 5 ml ofEtOH and 1 ml of DCM is heated s to reflux, 0.02 g ofN-methyl-D-glucamine is added and the mixture is left stirring for 1hour 30 minutes at RT. It is partially concentrated under vacuum andpoured into 15 ml of ether, and the precipitate formed is drained. 0.032g of the expected product is obtained, m.p.=90° C. (gum).

NMR (DMSO+TFA): 1:d:6H; 1.5-2.2:u.c.:14H; 2.5-2.6:mt:5H;2.6-3.2:u.c.:14H; 3.2-3.7:u.c.:13H; 3.85:mt:1H; 6.6:d:2H; 6.7:s:1H;7.1-7.4:u.c.:4H.

EXAMPLE 46

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid diethanolamine salt.

0.1 g of the compound obtained in EXAMPLE 1' is dissolved in 1.5 ml ofEtOH and 1.5 ml of DCM, 0.015 g of diethanolamine is added and themixture is left stirring for 30 minutes at RT and left overnight at 5°C. The crystallized product formed is drained. 0.03 g of the expectedproduct is obtained, m.p.=200° C. (dec.).

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:14H; 2.5:bs:2H;2.6-3.25:u.c.:16H; 3.3-3.8:u.c.+s:12H; 6.6:d:2H; 6.7:s:1H;7.1-7.4:u.c.:4H.

EXAMPLE 47

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid L(+)-tartrate.

A mixture of 0.1 g of the compound obtained in EXAMPLE 1' and 0.022 g ofL(+)-tartaric acid in 1.5 ml of EtOH and 1.5 ml of DCM is heated toreflux, 8 ml of EtOH are then added and refluxing is continued for 5minutes. After cooling to RT, the mixture is partially concentratedunder vacuum and poured into 10 ml of ether, and the precipitate formedis drained. 0.07 g of the expected product is obtained after drying overP₂ O₅, m.p.=154° C. (dec.).

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.4:u.c.:14H; 2.55:bs:2H; 2.6-3:u.c.:10H;3.1:mt:2H; 3.5:mt:2H; 3.65:s:6H; 4.35:s:2H; 6.6:d:2H; 6.75:s:1H;7.15-7.5:u.c.:4H.

EXAMPLE 48

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid choline salt.

A solution of 1 ml of DCM containing 0.05 g of the compound obtained inEXAMPLE 1' and 0.025 ml of a 45% solution of choline hydroxide in MeOHare left stirring for 15 minutes at 35° C., and the mixture is thenconcentrated under vacuum. The residue is triturated in 5 ml of etherand the precipitate formed is drained. 0.03 g of the expected product isobtained, m.p.=150° C.

NMR (DMSO+TFA): 1.05:d:6H; 1.4-2.2:u.c.:14H; 2.5:bs:2H; 2.4-3:u.c.:1OH;3.1:bs:11H; 3.4:mt:2H; 3.5:mt:2H; 3.6:s:6H; 3.8:mt:2H; 6.6:d:2H;6.7:s:1H; 7.1-7.4:u.c.:4H.

EXAMPLE 49

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid isethionate.

A mixture of 0.1 g of the compound obtained in EXAMPLE 1' in 3 ml of2-propanol is heated to reflux, 0.022 g of 83% isethionic acid (obtainedby elution of sodium isethionate on DOWEX®50 W×8 resin in H⁺ form) isadded and crystallization is allowed to take place overnight. Thecrystallized product formed is drained. 0.055 g of the expected productis obtained, m.p.=230° C.

NMR (DMSO+TFA): 1.05:d:6H; 1.55:u.c.:14H; 2.55:bs:2H; 2.6-3.05:u.c.:12H;3.1:mt:2H; 3.5:mt:2H; 3.6-3.7:s+mt:8H; 6.6:d:2H; 6.75:s:1H;7.15-7.45:u.c.:4H.

EXAMPLE 50

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid potassium salt.

A solution of 0.15 g of the compound obtained in EXAMPLE 1' and 0.03 gof potassium tert-butylate in 6.5 ml of 2-propanol is left overnight atRT and then concentrated under vacuum. The residue is dissolved in 0.5ml of MeOH, and this solution is poured into 25 ml of isopropyl ethercooled to -20° C. The precipitate formed is drained and dried over P₂ O₅at 80° C. 0.09 g of the expected product is obtained, m.p.=222° C.

This compound may also be obtained by following the procedure describedbelow.

1 ml of a solution of 0.129 g of KOH in 10 ml of MeOH is added to asolution of 0.1 g of the compound obtained in EXAMPLE 1' in 4 ml of DCM,and the mixture is then concentrated under vacuum. The residue isdissolved in 0.5 ml of 2-propanol, this solution is poured into 75 ml ofether cooled to 5° C. and the precipitate formed is drained. 0.015 g ofthe expected product is obtained.

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.3:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H;3.1:t:2H; 3.5:t:2H; 3.6:s:6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.5:u.c.:4H.

EXAMPLE 51

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid dihydrogen phosphate.

A mixture of 0.1 g of the compound obtained in EXAMPLE 1' and 0.017 g of85% orthophosphoric acid in 2 ml of DCM and 3 ml of EtOH is leftstirring for 1 hour at RT. It is partially concentrated under vacuum andpoured into 10 ml of ether cooled to 5° C., and the precipitate formedis drained. 0.04 g of the expected product is obtained after drying at60° C.

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:m:14H; 2.5:se:2H; 2.6-3.3:u.c.:12H;3.5:mt:2H; 3.6:s:6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.4:u.c.:4H.

EXAMPLE 52

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid 2-naphthalenesulphonate.

A solution of 0.5 g of the compound obtained in EXAMPLE 1' and 0.16 g of2-naphthalenesulphonic acid in 5 ml of MeOH is precipitated with 25 mlof ether cooled to 5° C., the precipitate formed is drained and thefiltrate is kept. The precipitate is dissolved in 2 ml of MeOH, thissolution is poured into 50 ml of ether cooled to 5° C., the precipitateformed is drained and 0.2 g of the expected product is obtained. Thefirst filtrate is precipitated with 50 ml of ether cooled to 5° C., theprecipitate formed is drained and 0.27 g of second crop of the expectedproduct is obtained.

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:14H; 2.5:bs:2H; 2.6-3:u.c.:10H;3.1:mt:2H; 3.5:mt:2H; 3.65:s:6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.6:u.c.:7H;7.7:d:1H; 7.8-8.1:u.c.:2H; 8.2:s:1H.

EXAMPLE 53

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-(2-diisopropylaminoethyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CONH(CH₂)₂ N(iPr)₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 0.53 g of the compound obtained in Preparation 4.30 and 2ml of SOCl₂ is left stirring for 4 hours at RT. It is concentrated undervacuum, the residue is taken up with DCM and the mixture is evaporatedunder vacuum, the residue is taken up with DCM and the solvent isevaporated off under vacuum. The acid chloride thereby obtained is usedwithout further treatment. Separately, a mixture of 0.19 g of compound Band 0.49 ml of bis(trimethylsilyl)acetamide in 2 ml of acetonitrile isheated to reflux under a nitrogen atmosphere for 35 minutes. Aftercooling to RT, a Solution of the acid chloride prepared above in 8 ml ofacetonitrile is added, and the mixture is left stirring overnight at RT.It is evaporated under vacuum, the residue is stirred with 8.8 ml ofMeOH, 8.8 ml of water are added and the mixture is evaporated undervacuum. The residue is treated with 1.2N HCl solution and theprecipitate formed is filtered off. The precipitate is treated with 10ml of water, the mixture is alkalinized to pH 8 by adding 1.3N NaOHsolution, and the precipitate is drained and washed with water. 0.475 gof the expected product is obtained after crystallization in the heatedstate in 40 ml of acetonitrile, m.p.=196°-198° C.

NMR (DMSO+TFA): 1.1:d:6H; 1.3:d:12H; 1.6-2.2:u.c.:12H; 2.55:u.c.:2H;2.7:mt:1H; 3.2:u.c.:2H; 3.5-3.8:u.c.+s:10H; 6.6:d:2H; 6.75:s:1H;7.2-7.4:mt:2H; 7.65:d:1H; 7.85:s:1H.

EXAMPLE 54

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N,N-bis(2-diethylaminoethyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CON(CH₂ CH₂ NEt₂)₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 0.4 g of the compound obtained in Preparation 4.34 and 2.5ml of SOCl₂ is left stirring for 24 hours at RT. It is concentratedunder vacuum, the residue is taken up with toluene and the solvent isevaporated off under vacuum. The acid chloride thereby obtained is usedwithout further treatment. Separately, a mixture of 0.18 g of compound Band 0.5 ml of bis(trimethylsilyl)acetamide in 4 ml of acetonitrile isheated to reflux for 45 minutes.

After cooling to RT, a solution of the acid chloride prepared above in 3ml of acetonitrile is added, and the mixture is left stirring for 72hours at RT. 3 ml of MeOH are added and the reaction mixture isconcentrated under vacuum. The residue is dissolved in 3 ml of 1.2N HCl,the solution is washed 3 times with AcOEt, the aqueous phase isneutralized to pH 6 by adding concentrated NaOH solution, and the gummyproduct formed is separated after settling has taken place. The gummyproduct is chromatographed on silica H, eluting with a DCM/MeOH/NH₄ OH(75:25:1.2; v/v/v) mixture. 0.4 g of the expected product is obtainedafter trituration in ether, m.p.=169° C.

EXAMPLE 55

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-(4-piperidyl)-carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride. ##STR112## AA(OH)=2-carboxy-2-adamantyl).

A mixture of 0.3 g of the compound obtained in

EXAMPLE 12, 0.05 g of palladium on charcoal (10% Pd) and 0.033 ml ofconcentrated HCl in 10 ml of MeOH and 4 ml of DMF is hydrogenated for 5days at RT and then for 4 days at 50° C., at atmospheric pressure. Thecatalyst is filtered off on Celite®and the filtrate is evaporated undervacuum. The residue is taken up with ether and the crystallized productformed is drained. 0.121 g of the expected product is obtained afterdrying over P₂ O₅ at 70° C. under vacuum, m.p.=252° C.

NMR (DMSO+TFA): 1.1:d:6H; 1.5-2.2:u.c.16H; 2.4-3.5:3mt+bs:7H; 3.6:s:6H;3.9-4.15:u.c.:1H; 6.6:d:2H; 6.7:s:1H; 7.1-7.4:mt:2H; 7.6:d:1H; 7.8:s:1H.

EXAMPLE 56

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-(1-ethyl-2-pyrrolidinylmethyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid. ##STR113## AA(OH)=₂ -carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 53, from 0.48 g of the compound obtained in Preparation 4.35 and2 ml of SOCl₂, followed by 0.18 g of compound B and 0.46 ml ofbis(trimethylsilyl)acetamide in 2 ml of acetonitrile. 0.2 g of theexpected product is obtained after recrystallization in 2-propanol,m.p.=212° C. (dec.).

NMR (DMSO+TFA): 0.9:bs:6H; 1.05:u.c.:3H; 1.3-2.1:u.c.:14H; 2.3:bs:2H;2.5:u.c.:1H; 2.9:u.c.:2H; 3.2-3.6:u.c.+s:11H; 6.4:d:2H; 6.5:bs:1H;7-7.3:u.c.:2H; 7.45:d:1H; 7.65:bs:1H.

EXAMPLE 57

2- 2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-(2,2,6,6-tetramethyl-4-piperidyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid. ##STR114## AA(OH)=2-carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 53, from 0.43 g of the compound obtained in Preparation 4.36 and2 ml of SOCl₂, followed by 0.15 g of compound B and 0.39 ml ofbis(trimethylsilyl)acetamide in 2 ml of acetonitrile. After stirring ofthe reaction mixture overnight at RT, the precipitate formed is drainedand washed with acetonitrile. The precipitate is taken up in 4 ml ofMeOH, 4 ml of water are added gradually and the mixture is concentratedunder vacuum. The residue is taken up with 1.2N HCl solution and theprecipitate is drained after trituration. The precipitate is taken up in3 ml of water, the mixture is alkalinized to pH 9 by adding 1.3N NaOHsolution, and the precipitate formed is drained and washed with water.0.24 g of the expected product is obtained after drying over P₂ O₅,m.p.=270°-272° C.

NMR (DMSO+TFA): 1.5:d:6H; 1.3:S:6H; 1.4:s:6H; 1.5-2.2:2u.c.:16H;2.65:mt:1H; 3.6:s:6H; 4.2-4.4:u.c.:1H; 6.55:d:2H; 6.7: s:1H;7.1-7.4:u.c.:2H; 7.6:d:1H; 7.8:s: 1H.

EXAMPLE 58

2- 5-(2,6-Dimethoxyphenyl)-1- 4-3-(diethylamino)-1-pyrrolidinyl!carbonyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid. ##STR115## AA(OH)=2-carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 53, from 0.39 g of the compound obtained in Preparation 4.41 and2 ml of SOCl₂, followed by 0.13 g of compound B and 0.34 ml ofbis(trimethylsilyl)acetamide in 2 ml of acetonitrile. After stirring ofthe reaction mixture overnight at RT, some insoluble matter is filteredoff and the filtrate is concentrated under vacuum. The residue is takenup in 5 ml of MeOH, 5 ml of water are added and the mixture isconcentrated under vacuum. The residue is taken up with 1.2N HClsolution and the crystals formed are drained. The crystals are dissolvedin water, the solution is alkalinized to pH 9 by adding 1.3N NaOH andthe precipitate formed is drained. 0.07 g of the expected product isobtained after recrystallization in acetonitrile, m.p.=175° C. (dec.).

NMR (DMSO+TFA): 1.0:d:6H; 1.1-1.3:u.c.:6H; 1.5-2.8:4u.c.:17H;2.8-4.2:3u.c.+1s:15H; 6.6:d:2H; 6.7:s:1H; 7.2-7.4:u.c.:3H; 7. 5:bs:1H.

EXAMPLE 59

2- 5-(2,6-Dimethoxyphenyl)-1- 4-4-(dimethylamino)-1-piperidyl!carbonyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid. ##STR116## AA(OH)=₂ -carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 53, from 0.45 g of the compound obtained in Preparation 4.37 and2 ml of SOCl₂, followed by 0.17 g of compound B and 0.43 ml ofbis(trimethylsilyl)acetamide in 2 ml of acetonitrile. 0.26 g of theexpected product is obtained after crystallization in the heated statein acetone and then in MEOW, m.p.=200° C. (dec.).

NMR (DMSO+TFA): 1.05:d:6H; 1.4-2.3:2u.c.:16H; 2.5:bs:2H; 2.7:s+mt:7H;2.8-3.8:2u.c.+s:10H; 4.4-4.8:u.c.:1H; 6.6:d:2H; 6.7:s:1H;7.1-7.4:u.c.:4H.

EXAMPLE 60

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(2-cyanoethyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CONMe(CH₂)₂ CN; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 53, from 3.48 g of the compound obtained in Preparation 4.38 and20 ml of SOCl₂ followed by 1.43 g of compound B and 3.6 ml ofbis(trimethylsilyl)acetamide in 25 ml of acetonitrile. After stirring ofthe reaction mixture overnight at RT, the mixture is concentrated undervacuum, the residue is taken up in 64 ml of MeOH, 64 ml of water areadded and the mixture is concentrated under vacuum. The residue is takenup in 1.2N HCl, and the precipitate formed is drained and washed with1.2N HCl. The precipitate is taken up in 5 ml of MeOH, the mixture isheated to reflux and allowed to cool to RT and the precipitate isdrained. 3.78 g of the expected product are obtained after drying overP₂ O₅, m.p.=249° C.

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:12H; 2.42-3.0:u.c.:8H;3.3-3.75:u.c.:8H; 6.58:d:2H; 6.73:s:1H; 7.1-7.42:u.c.:4H.

EXAMPLE 61

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-aminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CONMe(CH₂)₃ NH₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 1 g of the compound obtained in EXAMPLE 60, 10 ml of 20%ammonium hydroxide solution and 0.1 g of Raney® nickel in 20 ml of EtOHis hydrogenated for 4 hours at RT and at atmospheric pressure. Thecatalyst is filtered off on Celite® and washed with EtOH and then withMeOH, and the filtrate is partially concentrated. The crystallizedproduct formed is drained and the filtrate is concentrated under vacuum.The crystallized product and the concentration residue are taken up in1.2N HCl, and the precipitate is drained and washed with 1.2N HCl. Theprecipitate is dissolved in water, the aqueous phase is neutralized topH 7 by adding 1.3N NaOH, and the precipitate formed is drained, washedwith water and dried over P₂ O₅. The precipitate is taken up in2-propanol, the mixture is heated to reflux and allowed to cool to RTand the precipitate is drained. 0.54 g of the expected product isobtained after drying, m.p.=239-241° C.

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.2:u.c.:14H; 2.4-3.8:u.c.:8H; 3.5:mt:2H;3.64:s:6H; 6.6:d:2H; 6.72:s:1H; 7.1-7.45:u.c.:4H.

EXAMPLE 62

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(2-carbamoylethyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CONMe(CH₂)₂ CONH₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 0.2 g of the compound obtained in EXAMPLE 60, 0.12 ml of30% hydrogen peroxide solution in water and 0.18 ml of 6N NaOH in 10 mlof 95% EtOH is left stirring for 3 hours 30 minutes at RT. 0.06 ml ofthe 30% hydrogen peroxide solution and 0.06 ml of 6N NaOH are thenadded, and stirring is continued at RT for 1 hour 30 minutes. Someinsoluble matter is filtered off, water is added to the filtrate, theaqueous phase is washed twice with DCM, acidified to pH 3 by adding 1.2NHCl and extracted with DCM, the organic phase is dried over MgSO₄ andthe solvent is evaporated off under vacuum. The residue ischromatographed on silica H, eluting with a toluene/MeOH (90:10; v/v)mixture. 0.018 g of the expected product is obtained after triturationin ether, m.p.=164°-166° C.

EXAMPLE 63

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(2-carboxyethyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CONMe(CH₂)₂ CO₂ H; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 0.4 g of the compound obtained in EXAMPLE 60 and 0.042 mlof 4-methoxybenzyl alcohol in 3 ml of DCM is cooled to 0° C., a streamof HCl gas is bubbled through it for 30 minutes, and the reactionmixture is diluted by adding 17 ml of DCM and left stirring for 2 hoursat 0° C. It is concentrated under vacuum, the intermediate imidateobtained is taken up in 9 ml of acetone, 2 ml of 1.2N HCl are added andthe mixture is left stirring for 5 days at RT. 6 ml of DMF and 1 ml of1.2N HCl are added, and the mixture is heated to reflux for 3 days andleft stirring for 72 hours at RT. It is concentrated under vacuum, theresidue is taken up with DCM, the organic phase is extracted withsaturated NaHCO₃ solution, the aqueous phase is washed with DCM,acidified to pH 1 by adding concentrated HCl solution and extracted withDCM, the organic phase is dried over MgSO₄ and the solvent is evaporatedoff under vacuum. 0.03 g of the expected product is obtained aftertrituration in ether followed by drying at 60° C. over P₂ O₅,m.p.=166°-168° C.

NMR (DMSO+TFA): 1:d:6H; 1.5-1.9:u.c.:12H; 1.9-2.8:u.c.:5H;2.8-3.0:mt:3H; 3.2-3.6:mt:2H; 3.65:s:6H; 6.6:d:2H; 6.7:s:1H;7.0-7.5:u.c.:4H.

EXAMPLE 64

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-(2-propenyl)-carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CONHCH₂ CH═CH₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 53, from 1.49 g of the compound obtained in Preparation 4.42 and25 ml of SOCl₂, followed by 0.65 g of compound B and 1.6 ml ofbis(trimethylsilyl)acetamide in 10 ml of acetonitrile. After stirringovernight at RT, some insoluble matter is filtered off and the filtrateis concentrated under vacuum. The residue is taken up in 10 ml of MeOH,10 ml of water are added, and the solid product is drained and washedwith MeOH. The solid product is taken up in acetonitrile, the mixture isheated to reflux and allowed to cool to RT, and the precipitate isdrained and dried over P₂ O₅. 1.6 g of the expected product areobtained, m.p.=304° C.

NMR: 1.1:d:6H; 1.5-2.2:u.c.:12H; 2.5:bs:2H; 2.65:qt:1H; 3.65:s:6H;3.9:t:2H; 5.0-5.2:u.c.:2H; 5.8-6.0:u.c.:1H; 6.6:d:6.7:s:1H;7.1-7.4:u.c.:3H; 7.6:d:1H; 7.85:s:1H; 8.7:t:1H.

EXAMPLE 65

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-trimethylammoniopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid iodide. ##STR117## AA(OH)=2-carboxy-2-adamantyl).

A mixture of 0.1 g of the compound obtained in EXAMPLE 1' and 0.04 g ofmethyl iodide in 6 ml of DCM is left Stirring for 24 hours at RT. It isconcentrated under vacuum, the residue is triturated in ether and theprecipitate formed is drained. 0.12 g of the expected product isobtained, m.p.=222° C.

NMR (DMSO+TFA): 1.05:d:6H; 1.5-2.3:u.c.:14H; 2.5:bs:2H; 2.7:qt:1H;2.75-3.7:u.c.:22H; 6.6:d:2H; 6.7:s:1H; 7.1-7.5:u.c.:4H.

EXAMPLE 66

2- 5-(2,6-Dimethoxyphenyl)-1- 4- N-methyl-N- 3-N'-methyl-N'-(tert-butoxycarbonyl)amino!propyl!-carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-CONMe(CH₂)₃ N(Me)COOtBu; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

A solution of 1.17 g of the compound obtained in Preparation 4.43 and0.3 ml of triethylamine in 3 ml of DMF is cooled to -10° C., 0.21 ml ofethyl chloroformate is added under a nitrogen atmosphere and the mixtureis left stirring for 15 minutes at -10° C. Separately, a mixture of 0.77g of compound B and 2 ml of bis(trimethylsilyl)acetamide in 3 ml of DMFis heated at 80° C. for 45 minutes. After cooling to RT, this solutionis added to the solution of mixed anhydride prepared above, and themixture is left stirring for 3 days at RT. Some insoluble matter isfiltered off and the filtrate is concentrated under vacuum. The residueis taken up with 32 ml of MeOH, 32 ml of water are added gradually andthe mixture is concentrated under vacuum. The residue is taken up withwater, and the crystallized product formed is drained, washed with waterand dried. The crystals are taken up with DCM, some insoluble matter isfiltered off and the filtrate is chromatographed on silica, eluting witha DCM/MeOH mixture from (100:0.5; v/v) to (100:2.5; v/v). 1 g of theexpected product is obtained after trituration in pentane, m.p.=118-120°C.

EXAMPLE 67

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-methylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-CONMe(CH₂)₃ NHMe; R₂ =2-iPr; R₃ =H; R₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 0.6 g of the compound obtained in EXAMPLE 66 and 4.2 ml ofconcentrated HCl solution in 2.7 ml of MeOH and 1.8 ml of water is leftstirring for 20 minutes at RT. EtOH is added and the reaction mixture isconcentrated under vacuum. The residue is taken up with EtOH and thesolvent is evaporated off under vacuum. The residue is taken up withether, and the precipitate formed is drained and washed with ether. 0.51g of the expected product is obtained after drying under vacuum at 60°C., m.p.=240° C.

NMR (DMSO+TFA): 1.1:d:6H; 1.5-2.4:u.c.:14H; 2.6:d:3H; 2.7:mt:1H;2.8-3.6:u.c.+s:7H; 3.65:s:6H; 6.6:d:2H; 6.7:s:1H; 7.1-7.45:u.c.:4H.

EXAMPLE 68

2- 5-(2,6-Dimethoxyphenyl)-1-4-(4-methylphenylsulphonylamino)-2-isopropylphenyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylicacid. ##STR118## AA(OH)=₂ -carboxy-2-adamantyl).

A mixture of 0.92 g of the compound obtained in Preparation 4.44 and 7ml of SOCl₂ in 7 ml of DCM is heated for 1 hour at 40° C. It isconcentrated under vacuum, and the acid chloride thereby obtained isused without further treatment. Separately, a mixture of 0.54 g ofcompound B and 1.35 ml of bis(trimethylsilyl)acetamide in 5 ml ofacetonitrile is heated to reflux for 1 hour. After cooling to RT, thissolution is added to the acid chloride prepared above, 0.25 ml oftriethylamine is added and the mixture is left stirring for 2 hours atRT. It is concentrated under vacuum, the residue is taken up with 10%HCl solution, the mixture is extracted with DCM, the organic phase isdried over Na₂ SO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica H, eluting with a DCM/MeOH/H₂ O(100:3:0.5; v/v/v) mixture. 0.9 g of the expected product is obtained.

NMR (DMSO+TFA): 0.85:d:6H; 1.52-2.25:u.c.:12H; 2.34:s:3H;2.45-2.06:u.c.:3H; 3.55:s:6H; 6.55:d:2H; 6.65:s:1H; 6.84:dd:1H;6.95-7.05:u.c.:2H; 7.23-7.36:u.c.:3H; 7.58:d:2H.

EXAMPLE 69

2- 5-(2,6-Dimethoxyphenyl)-1- 4-3-(diethylamino)propanoylamino!-2-isopropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-NHCO(CH₂)₂ NEt₂ ; R₂ =2-iPr; R₃ =H; R₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 68, from 0.27 g of the compound obtained in Preparation 4.46 in5 ml of SOCl₂ and 5 ml of DCM on the one hand, and on the other hand0.155 g of compound B and 0.39 ml of bis(trimethylsilyl)acetamide in 2ml of acetonitrile and 0.14 ml of triethylamine. 0.13 g of the expectedproduct is obtained, m.p.=180° C.

NMR (DMSO+TFA): 1.05:d:6H; 1.25:t:6H; 1.55-2.22:u.c.:12H;2.5-2.72:u.c.:3H; 2.85:t:2H; 3.2:qr:4H; 3.4:mt:2H; 3.68:s:6H; 6.6:d:2H;6.72:s:1H; 7.15:d:1H; 7.25-7.5:u.c.:2H; 7.58:d:1H.

EXAMPLE 70

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-acetyl-N-(3-diethylaminopropyl)amino!-2-isopropylphenyl!-3-pyrazolyl-carbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-N(COMe)(CH₂)₃ NEt₂ ; R₂ =2-iPr; R₃ =H; R₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 68, from 0.38 g of the compound obtained in Preparation 4.48 and3 ml of SOCl₂ in 3 ml of DCM, followed by 0.164 g of compound B and 0.36ml of bis(trimethylsilyl)acetamide in 2 ml of acetonitrile and 0.075 mlof triethylamine. 0.24 g of the expected product is obtained, m.p.=220°C.

NMR (DMSO+TFA): 1.0:d:6H; 1.5:t:6H; 1.45-2.2:u.c.:17H; 2.5-2.72:u.c.:3H;2.9-3.15:u.c.:6H; 3.6:s:6H; 3.7:t:2H; 6.59:d:2H; 6.74:s:1H;7.15-7.42:u.c.:5H.

EXAMPLE 71

2- 5-(2,6-Dimethoxyphenyl)-1- 4-(3-diethylamino-propyl)amino!-2-isopropylphenyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylicacid.

(I: R₁ =4-NH(CH₂)₃ NEt₂ ; R₂ =2-iPr; R₃ =H; R₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 0.2=of the compound obtained in EXAMPLE 70 and 1 ml ofconcentrated HCl in 5 ml of water and 5 ml of EtOH is heated to refluxfor 16 hours. Water is added, the pH is adjusted to 5 by adding 10% NaOHand the precipitate is drained. 0.145 g of the expected product isobtained, m.p.=180° C.

NMR (DMSO+TFA): 1.05:d:6H; 1.19:t:6H; 1.4-2.2:u.c.:14H;2.4-2.63:u.c.:3H; 2.98-3.3:u.c.:8H; 3.62:s:6H; 6.5-6.85:u.c.:5H;7.05:d:1H; 7.3:t:1H.

EXAMPLE 72

2- 5- 2-(Cyclopropylmethyloxy)-6-methoxyphenyl!-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantane-carboxylicacid hydrochloride. ##STR119## AA(OH)=₂ -carboxy-2-adamantyl).

A mixture of 3.87 g of the compound obtained in Preparation 4.49 and 2.4ml of SOCl₂ in 50 ml of DCM is heated at 60° C. for 8 hours. It isconcentrated under vacuum, the residue is taken up with toluene and thesolvent is evaporated off under vacuum. The acid chloride therebyobtained is used without further treatment. Separately, a mixture of1.27 g of compound B and 2.65 g of bis(trimethylsilyl)acetamide in 80 mlof acetonitrile is heated at 80° C. for 3 hours. A solution of the acidchloride prepared above in 80 ml of acetonitrile is then added and themixture is heated at 60° C. for 3 hours. Some insoluble matter isfiltered off and the filtrate is concentrated under vacuum. The residueis taken up in 16 ml of MeOH, 16 ml of water is added and the mixture isconcentrated under vacuum. The residue is taken up with water, themixture is extracted with DCM, the organic phase is dried over Na₂ SO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H, eluting with a DCM/MeOH/H₂ O (100:5:0.5;v/v/v) mixture. 2.1 g of the expected product are obtained.

EXAMPLE 73

2- 5-(2-Hydroxy-6-methoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-CONMe(CH₂)₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =H; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 1 g of the compound obtained in EXAMPLE 72 and 20 ml ofMeOH and 20 ml of HCl is heated at 60° C. for 5 hours. It isconcentrated under vacuum, the residue is taken up with toluene and themixture is concentrated under vacuum. The residue is chromatographed onsilica H, eluting with a DCM/MeOH (90:10; v/v) mixture and then with aDCM/MeOH/NH₄₀ H (80:20:2; v/v/v) mixture. 0.6 g of the expected productis obtained, m.p. >250° C.

EXAMPLE 74

2- 5-(2,6-Dimethoxyphenyl)-1- 4-3-(diethylaminopropanoyl)amino!-2-methylphenyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylicacid.

(I: R₁ =4-NHCO(CH₂)₂ NEt₂ ; R₂ =2-Me; R₃ =H; R₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

A) 2-5-(2,6-Dimethoxyphenyl)-1-(2-methyl-4-nitrophenyl)-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

This compound is prepared according to the procedure described inEXAMPLE 68, from 3.2 g of the compound obtained in Preparation 4.50 and20 ml of SOCl₂ in 40 ml of DCM, followed by 2.4 g of compound B and 6 mlof bis(trimethylsilyl)acetamide in 15 ml of acetonitrile and then 1.1 mlof triethylamine. After stirring overnight at RT, the mixture isconcentrated under vacuum, the residue is taken up in an acetone/watermixture, and the precipitate formed is drained and dried. Theprecipitate is chromatographed on silica H, eluting with a DCM/MeOH/H₂ O(100:3:0.2; v/v/v) mixture. 4.3 g of the expected product are obtained,m.p.=150° C.

NMR: 1.6-2.2:u.c.:12H; 2.25:s:3H; 2.62:mt:2H; 3.63:s:6H; 6.68:d:2H;6.88:s:1H; 7.03-7.43:u.c.:2H; 7.58:s:1H; 8.05:dd:1H; 8.28:d:1H;12.4:bs:1H.

B) 2-5-(2,6-Dimethoxyphenyl)-1-(4-amino-2-methylphenyl)-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

A mixture of 4.2 g of the compound obtained in the preceding step and0.5 g of Raney® nickel in 40 ml of MeOH and 2 ml of DMF is hydrogenatedfor 4 hours at RT and at atmospheric pressure. The catalyst is filteredoff and the filtrate is concentrated under vacuum. The residue is takenup with ether and the precipitate formed is drained. 3.37 g of theexpected product are obtained, m.p.=205° C.

NMR: 1.42-2.1:u.c.:15H; 2.52:mt:2H; 3.57:s:6H; 5.1:bs:2H; 6.1:dd:1H;6.22:d:1H; 6.42-6.68:u.c.:4H; 7.17-7.25:u.c.:2H.

C) 2- 5-(2,6-Dimethoxyphenyl)-1- 4-3-(diethylaminopropanoyl)amino!-2-methylphenyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylicacid.

A mixture of 0.3 ml of 3-diethylaminopropanoic acid hydrochloride and 3ml of SOCl₂ in 6 ml of DCM is heated at 35° C. for 45 minutes and thenconcentrated under vacuum. The acid chloride thereby obtained is addedto a solution of 0.87 g of the compound obtained in the preceding stepand 0.157 ml of triethylamine in 5 ml of DCM. The mixture isconcentrated under vacuum and the residue is chromatographed on silicaH, eluting with a DCM/MeOH/H₂ O (100:5:0.5; v/v/v) mixture. 0.5 g of theexpected product is obtained, m.p.=190° C.

NMR: 1.28:t:6H; 1.6-2.22:u.c.:15H; 2.5-3.2:u.c.:10H; 3.6:s:6H;6.63:d:2H; 6.75:s:1H; 7.05:d:1H; 7.28-7.48:u.c.:3H; 7.55:d:1H;10.18:s:1H.

EXAMPLE 75

2- 5-(2,6-Dimethoxyphenyl)-1- 4-3-(1-piperidyl)propanoyl!amino!-2-methylphenyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylicacid. ##STR120## AA(OH)=₂ -carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 74, step C, from 0.1 g of 3-(1-piperidyl)propanoic acid and 1 mlof SOCl₂ in 2 ml of DCM, followed by 0.337 g of the compound obtained instep B of EXAMPLE 74 and 0.17 ml of triethylamine in 5 ml of DCM. 0.2 gof the expected product is obtained, m.p.=240° C.

NMR: 1.22-2.1:u.c.:21H; 2.22-2.38:u.c.:10H; 3.58:s:6H; 6.5:d:2H;6.6:s:1H; 6.9:d:1H; 7.18-7.3:u.c.:3H; 7.38:d:1H; 10.1:s:1H.

EXAMPLE 76

2- 5-(2,6-Dimethoxyphenyl)-1- 4-3-(diethylamino)propanoylamino!-2-isobutylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

(I: R₁ =4-NHCO(CH₂)₂ NEt₂ ; R₂ =2-iBu; R₃ =H; R₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 68, from, on the one hand 0.15 g of the compound obtained inPreparation 4.52 and 2 ml of SOCl₂ in 2 ml of DCM, and on the other hand0.084 g of compound B and 0.21 ml of bis-(trimethylsilyl)acetamide in 2ml of acetonitrile and 0.79 ml of triethylamine. 0.014 g of the expectedproduct is obtained, m.p.=180-200° C.

NMR: 0.75:d:6H; 1.15:t:6H; 1.4-2.25:u.c.:15H; 2.5:s:2H; 2.8:t:2H;3.1:qr:4H; 3.3:t:2H; 3.55:s:6H; 6.5:d:2H; 6.6:s:1H; 6.8-7.6:u.c.:5H;10.3:s:1H.

EXAMPLE 77

2- 5-(2,6-Dimethoxyphenyl)-1- 4-3-(diethylamino)propanoylamino!-2-cyclopentylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid. ##STR121## AA(OH)=2-carboxy-2-adamantyl).

This compound is prepared according to the procedure described inEXAMPLE 68, from, on the one hand, 0.32 g of the compound obtained inPreparation 4.54 and 2 ml of SOCl₂ in 5 ml of DCM, and on the other hand0.17 g of compound B and 0.42 ml of bis-(trimethylsilyl)acetamide in 2ml of acetonitrile and 0.154 ml of triethylamine. 0.035 g of theexpected product is obtained, m.p.=175-185° C.

NMR (DMSO+TFA): 1.1-2.55:u.c.:26H; 2.5-2.75:u.c.:5H; 3.15:mt:4H;3.35:mt:2H; 3.62:s:6H; 6.55:d:2H; 6.65:s:1H; 7.03:d:1H; 7.25:t:1H;7.35:dd:1H; 7.55:d:1H.

EXAMPLE 78

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-(2-diethylaminoethyl)carbamoyl!-3-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-CONH(CH₂)₂ NEt₂ ; R₂ =3-iPr; R₃ =H; R₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 0.36 g of the compound obtained in Preparation 4.55 and 5ml of SOCl₂ in 15 ml of chloroform is left stirring overnight at RT. Itis concentrated under vacuum, the residue is taken up with toluene andthe mixture is concentrated under vacuum. The acid chloride therebyobtained is used without further treatment. Separately, a mixture of0.123 g of compound B and 0.315 ml of bis(trimethylsilyl)acetamide in 10ml of acetonitrile is heated to reflux for 30 minutes. This solution isadded to a solution of the acid chloride prepared above in 15 ml ofacetonitrile, and the mixture is heated to reflux for 3 hours. It isconcentrated under vacuum, the residue is taken up in 15 ml of MeOH and5 ml of water and the mixture is left stirring for 2 hours at RT. It isconcentrated under vacuum, the residue is extracted with chloroform, theorganic phase is washed with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. 0.35 g of the expected productis obtained after crystallization in chloroform, m.p.=210° C. (dec.)(the product crystallizes with 1 mol of chloroform).

EXAMPLE 79

2- 5-(2,6-Dimethoxyphenyl)-1-4-(2-aminoacetylamino)-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-NHCOCH₂ NH₂ ; R₂, R₃ =--(CH₂)₄ -; ₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

A) 2-5-(2,6-Dimethoxyphenyl)-1-(4-nitro-5,6,7,8-tetrahydro-1-naphthyl)-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

This compound is prepared according to the procedure described inEXAMPLE 15, from 4 9 of the compound obtained in Preparation 4.56 and 20ml of SOCl₂ in 20 ml of DCM, followed by 2.74 g of compound B and 6.86ml of bis(trimethylsilyl)acetamide in 20 ml of acetonitrile and 0.8 mlof triethylamine. After concentration under vacuum, the residue is takenup in EtOH and the precipitate formed is drained. The precipitate istaken up in MeOH, drained and washed with ether. 5.3 g of the expectedproduct are obtained.

NMR (DMSO+TFA): 1.5-2.25:u.c.:16H; 2.42-2.65:u.c.:4H; 2.8:mt:2H;3.6:s:6H; 6.61:d 2H; 6.75:s:1H; 7.06:d:1H; 7.3:t:1H; 7.4: s:1H;7.65:d:1H.

B) 2-5-(2,6-Dimethoxyphenyl)-1-(4-amino-5,6,7,8-tetrahydro-1-naphthyl)-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

A mixture of 3 g of the compound obtained in the preceding step and 0.5g of Raney® nickel in 200 ml of DMF is hydrogenated at RT and atatmospheric 2o pressure. The catalyst is filtered off and the filtrateis concentrated under vacuum. The residue is taken up with water and theprecipitate formed is drained. 2.16 g of the expected product areobtained after drying.

NMR (DMSO+TFA): 1.42-2.2:u.c:16H; 2.3-2.8:u.c.:6H; 3.6:s:6H; 6.55:d:2H;6.7:s: 1H; 6.98:d:1H; 7.12:d:1H; 7.25:t:1H.

C) 2- 5-(2,6-Dimethoxyphenyl)-1- 4-2-(tert-butoxy-carbonylamino)acetylamino!-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

A mixture of 0.3 g of the compound obtained in the preceding step and0.258 ml of bis(trimethylsilyl)-acetamide in 2 ml of toluene is heatedfor 1 hour at 60° C. After cooling to RT, 0.64 ml of Boc-glycineN-carboxy anhydride and 0.006 ml of N-methylmorpholine are added and themixture is left stirring overnight at RT. A pH 4 buffer solution isadded, the mixture is extracted with AcOEt, the organic phase is driedover Na₂ SO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H, eluting with a DCM/MeOH mixture from(100:1; v/v) to (100:5; v/v). 0.14 g of the expected product isobtained.

NMR (DMSO+TFA): 1.32:s:9H; 1.45-2.12: u.c.:16H; 2.35-2.6:u.c.:6H;3.55:s:6H; 3.65: s:2H; 6.5:d:2H; 6.62:s:1H; 6.83:d:1H; 7.13-7.3:u.c.:3H.

D) 2- 5-(2,6-Dimethoxyphenyl)-1-4-(2-aminoacetylamino)-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylicacid hydrochloride.

A mixture of 0.14 g of the compound obtained in the preceding step and 5ml of concentrated HCl in 5 ml of MeOH is left stirring for 30 minutesat RT. Water is added, and the precipitate formed is drained and dried.0.06 g of the expected product is obtained, m.p.=220° C.

NMR: 1.59-2.5:u.c.:16H; 2.42-2.75:u.c.: 6H; 3.7:s:6H; 3.88:mt:2H;6.68:d:2H; 6.75: s:1H; 6.95:d:1H; 7.2-7.48:u.c.:3H; 8.2:mt: 1H;9.85:s:1H; 12.4:bs:1H.

EXAMPLE 80

2- 5-(2,6-Dimethoxyphenyl)-1- 4-(3-diethylaminopropanoyl)amino!-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-NHCO(CH₂)₂ NEt₂ ; R₂, R₃ =--(CH₂)₄ -; R₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

A mixture of 0.16 g of 3-diethylaminopropanoic acid hydrochloride and 2ml of SOCl₂ in 2 ml of DCM is heated at 40° C. for 1 hour. It isconcentrated under vacuum, the residue is taken up with DCM and themixture is added at RT to a solution of 0.5 g of the compound obtainedin step B of EXAMPLE 79 and 0,124 ml of triethylamine in 3 ml of DCM.After stirring over-night at RT, water is added, the mixture isextracted with DCM, the organic phases are dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H, eluting with a DCM/MeOH (100:3; v/v) mixture; 0.11 g of theexpected product is obtained.

NMR (DMSO+TFA): 1.21:t:6H; 1.41-2.2: u.c.:16H; 2.35-2.7:u.c.:6H;2.84:t:2H; 3.01-3.12:u.c.:4H; 3.35:t:2H; 3.6:s:6H; 6.55:d 2H; 6.7:s:1H;6.9:d:1H; 7.12-7.3:u.c.:2H.

EXAMPLE 81

2- 5-(2,6-Dimethoxyphenyl)-1-4-(2-aminoethylsulphonylamino)-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

(I: R₁ =4-NHSO₂ (CH₂)₂ NH₂ ; R₂, R₃ =--(CH₂)₄ -; R₄ =Me; AA(OH)=₂-carboxy-2-adamantyl).

A) 2-Phthalimidoethanesulphonic acid potassium salt.

This compound and the one of step B are prepared according to J. Am.Chem. Soc., 1947, 69, 1393-1401.

A mixture containing 30 g of taurine, 25 g of potassium acetate and 90ml of acetic acid is brought to reflux for 10 minutes and 37.8 g ofphthalic anhydride are then added. The mixture is heated to reflux fortwo and a half hours and then filtered, and the product is washed withAcOH and then with 2-propanol; it is rinsed with ether and then driedunder vacuum to obtain 59.14 g of the expected product.

B) 2-Phthalimidoethanesulphonyl chloride.

60 g of the compound obtained in step A in 300 ml of toluene are heatedto reflux for 1 hour in the presence of 30.7 g of phosphoruspentachloride. 30.7 g of phosphorus pentachloride are added again andrefluxing is maintained for 90 minutes. 280 g of ice are added to thereaction medium, the mixture is stirred, and the insoluble matter isfiltered off and then washed with ice-cold water. The residue is driedover P₂ O₅ and then recrystallized in dichloroethane to obtain 32 g ofthe expected product, m.p.=160° C.

C) 2- 5-(2,6-Dimethoxyphenyl)-1-4-(2-phthalimidoethylsulphonyl)-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

A mixture containing 0.5 g of the compound obtained in EXAMPLE 79, stepB, 0.43 ml of bis(tri-methylsilyl)acetamide and 5 ml of acetonitrile isleft stirring at 70° C. for 1 hour. The mixture is allowed to return toRT, and 0.63 g of the compound obtained in step B and 0.30 ml oftriethylamine are then added. After 2 hours with stirring at RT, themixture is acidified with 10% HCl solution. The mixture is filtered andthe residue is then dried over P₂ O₅ to obtain 0.9 g of the expectedproduct in crude form. It is recrystallized in 100% EtOH and decolorizedon animal charcoal in DCM. The product obtained is chromatographed onsilica H, eluting with a DCM/MeOH/H₂ O (100:2:0.2; v/v/v) mixture toobtain 0.28 g of the expected product.

NMR (DMSO+TFA): 1.45-2.15:u.c.:16H; 2.4-2.6:u.c.:4H; 2.75:mt:2H;3.48:s:6H; 3.95-4.15:u.c.:4H; 6.46:d:1H; 6.75:s:1H; 6.9:d 1H;7.1-7.3:u.c.:2H; 7.7-7.85:u.c.:4H.

D) 2- 5-(2,6-Dimethoxyphenyl)-1-4-(2-aminoethylsulphonylamino)-5,6,7,8-tetrahydro-1-naphthyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

A mixture containing 0.24 g of the compound obtained in the precedingstep, 2 ml of 95% EtOH and 23=1 of hydrazine hydrate is heated to refluxfor 2 hours. The reaction medium is diluted with MeOH, the crystals arethen filtered off and heated to reflux in water and the mixture isfiltered in the heated state. The crystals obtained are dried over P₂O₅. They are redissolved in MeOH, ethereal hydrogen chloride is added,the mixture is evaporated to dryness and the residue is then taken upwith ether and pentane. The mixture is filtered to obtain 60 mg of theexpected product.

NMR (DMSO+TFA): 1.48-2.18:u.c.:16H; 2.18-2.62:u.c.:4H; 2.7:mt:2H;3.19:mt:2H; 3.41:mt:2H; 3.62:s:6H; 6.58:d:1H; 6.7:s: 1H; 6.82:d:1H;7.08:d:1H; 7.28:t:1H; 7.39: s:1H.

EXAMPLE 82

(R)-2-Cyclohexyl-2- 5-(2,6-dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-iso-propylphenyl!-3-pyrazolylcarbonylamino!aceticacid.

(I: R₁ =4-CON(Me)(CH₂)₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ;AA(OH)=(R)-(α-carboxy)cyclohexylmethyl).

1.2 g of sodium hydroxide in 20.2 ml of water and 1.62 g ofcyclohexyl-D-glycine trifluoroacetate are mixed. 1.58 g of acid chlorideprepared in EXAMPLE 1, step A in 40 ml of anhydrous THF are addeddropwise, and the mixture is left stirring for 48 hours at RT. Themedium is concentrated, ice is added and the pH is adjusted to 7 byadding concentrated HCl. The mixture is filtered, and the residue iswashed with water and then with pentane and dried under vacuum. Theproduct is ground and then stirred in a water/DCM mixture. The resultingmixture is filtered, the aqueous phase is then extracted with DCM andthe organic phase is dried over Na₂ SO₄. The residue is concentrated,and the product is stirred in pentane and filtered off again. 380 mg ofthe expected product are obtained, m.p.=160° C.

EXAMPLE 83

(S)-2-Cyclohexyl-2- 5-(2,6-dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!aceticacid hydrochloride.

(I: R₁ =4-CON(Me)(CH₂)₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ;AA(OH)=(S)-(α-carboxy)cyclohexylmethyl).

A mixture containing 0.57 g of (S)-cyclohexylglycine and 1.49 g ofbis(trimethylsilyl)acetamide in 39 ml of acetonitrile is heated at 80°C. for 3 hours, and a solution of 1.93 g of the acid chloride preparedin EXAMPLE 1, step A, in 39 ml of acetonitrile is added dropwise. After3 hours at 60° C., the mixture is allowed to return to RT and is thenfiltered, and the filtrate is concentrated. 8 ml of MeOH and 3 ml ofwater are added to the residue and the mixture is left stirring for 30minutes. 5 ml of water are added and the mixture is concentrated. Theoil formed is taken up in DCM, and the organic phase is washed withsaturated NaCl solution, dried over Na₂ SO₄ and concentrated. Theresidue is taken up in isopropyl ether and filtered to obtain 1.12 g ofthe expected compound, m.p.=160° C.

EXAMPLE 84

9- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!bicyclo3.3.1!nonane-9-carboxylic acid.

(I: R₁ =4-CON(Me)(CH₂)₃ NMe₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ;AA(OH)=9-carboxybicyclo 3.3.1!nonan-9-yl).

585 mg of 9-aminobicyclo 3.3.1!nonane-9-carboxylic acid and 1.5 ml ofbis(trimethylsilyl)-acetamide in 39 ml of acetonitrile are mixed, andthe mixture is heated at 80° C. for 3 hours. 1 equivalent of the acidchloride prepared in EXAMPLE 1, step A in 39 ml of acetonitrile is addeddropwise, and the mixture is heated at 60° C. for 3 hours. After 12hours at RT, the insoluble matter is filtered off, the filtrate is thenconcentrated and the residue is stirred thereafter with 8 ml of MeOH and8 ml of water. The mixture is concentrated again and the residue is thenextracted with DCM to obtain 900 mg of the expected product, m.p.=160°C.

EXAMPLE 85

2- 5-(2,6-Dimethoxyphenyl)-1- 5-(3-diethylaminopropanoyl)amino!-2-isopropylphenyl!-3-pyrazolylcarbonyl-amino!-2-adamantanecarboxylicacid.

(I: R₁ =5-NHCO(CH₂)₂ NEt₂ ; R₂ =2-iPr; R₃ =H; R₄ =CH₃ ; AA(OH)=₂-carboxy-2-adamantyl).

The acid chloride is prepared from 0.95 g of the compound of Preparation4.57 in 5 ml of thionyl chloride and 15 ml of DCM by heating to refluxfor 1 hour followed by evaporation.

A mixture of 0.55 g of compound B, 1.37 ml ofbis(trimethylsilyl)acetamide in 5 ml of acetonitrile and the acidchloride in solution in 5 ml of DCM and 0.5 ml Of triethylamine isheated to reflux for 1 hour. After 2 hours of stirring at RT, themixture is evaporated to dryness and the residue is then stirred with 10ml of water, the mixture is extracted with DCM, the organic phase isdried over MgSO₄ and evaporated to dryness and the residue iscrystallized in acetone to obtain 0.55 g of the expected product.

NMR (DMSO+TFA): 0.8-1.35:u.c.:12H; 1.5-2.4:u.c.:12H; 2.4-2.6:u.c.:3H;2.8:t:2H; 3.15:qr:4H; 3.3:t:2H; 3.5:s:6H; 6.55:d: 2H; 6.65:s:1H;7.15-7.4:u.c.:3H; 7.75:d:1H.

EXAMPLE 86

Internal salt of 2- 5-(2,6-dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-iso-propylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid.

The compound may also be prepared from the compound of EXAMPLE 61according to the following procedure.

A mixture containing 0.2 g of the compound of EXAMPLE 61, 0.33 ml offormic acid and 0.11 ml of formaldehyde is heated at 100° C. for 30minutes. After 2 hours at RT, 1 ml of 2N HCl is added, and DCM andmethanol are then added in order to dissolve the gum formed. Thesolvents are evaporated off, the residue is taken up with water, and themixture is then neutralized with 1.3N sodium hydroxide to pH 7 whilecooling the medium in ice. The mixture is filtered, and the residue isrinsed with water and then dried over P₂ O₅ to obtain 0.13 g of theexpected product.

EXAMPLE 87

2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

Another method of preparation of the compound of EXAMPLE 1 is describedbelow.

A) 2-(Benzyloxycarbonylamino)-2-adamantanecarboxylic acid.

1.015 g of 2-amino-2-adamantanecarboxylic acid and 6 ml ofbis(trimethylsilyl)acetamide in 10 ml of DCM is heated to reflux for oneand a half hours. 0.75 ml of benzyloxycarbonyl chloride is added and themixture is heated at 50° C. for 15 minutes. The reaction medium iscooled to -70° C., decomposition is then effected by adding ice and themixture is extracted with AcOEt. The organic phase is washed with water(twice) and with brine, dried over MgSO₄ and evaporated under vacuum.The product crystallizes in hexane; 1.164 g are obtained.

NMR (DMSO+TFA): 1.5:d:2H; 1.8:u.c.: 6H; 2:t:4H; 2.4-2.5:u.c.:2H; 5:s:2H;7.3: bs:5H.

B) 2-(Benzyloxycarbonylamino)-2-adamantanecarboxylic acid tert-butylester.

1.164 g of the compound of the preceding step are dissolved in 15 ml ofDCM, 100 mg of hydrated paratoluenesulphonic acid are added, the mixtureis then cooled to -78° C. and a solution of isobutylene in 15 ml of DCMis added. The mixture is allowed to return to RT and is stirred for 24hours.

50 μl of concentrated sulphuric acid are added to dissolve the solid,after 5 hours the medium is cooled, saturated NaHCO₃ solution is thenadded, and the organic phase is dried over MgSO₄ and evaporated undervacuum. The residue is chromatographed on silica, eluting with ahexane/AcOEt (80:20; v/v) mixture, and 612 mg of the expected compoundare obtained.

NMR (CDCl₃): 1.4:s:9H; 1.5-1.9:u.c.: 8H; 2:t:4H; 2.5:s:2H; 4.9:s:1H;5.1:s: 2H; 7.2-7.4:u.c.:5H.

C) 2-Amino-2-adamantanecarboxylic acid tert-butyl ester hydrochloride.

600 mg of the product of the preceding step are dissolved in 40 ml ofEtOH, 150 μl of concentrated HCl and then 80 mg of Pd/C are added andthe medium is then hydrogenated. After 1 hour, the catalyst is filteredoff and the solvent is evaporated off to obtain 503 mg of the expectedproduct.

NMR (CD3OD):1.6:s:9H; 1.8-2:u.c.:8H; 2-2.2:u.c.:4H; 2.4:s:2H.

D) 5-(2,6-Dimethoxyphenyl)-1- 4- N-methyl-N- 3-N'-methyl-N'-(benzyloxycarbonyl)amino!propyl!carbamoyl!-2-isopropylphenyl!-3-pyrazolecarboxylicacid methyl ester.

0.33 g of the compound of Preparation 3.57 is dissolved in 20 ml ofmethanolic hydrogen chloride. After 72 hours with stirring, the solventsare evaporated off. The hydrochloride obtained is dissolved in 5 ml ofDCM, and 0.5 ml of triethylamine and 150 μl of benzyloxycarbonylchloride are then added. After one hour, the reaction medium isconcentrated under vacuum I₅ and the residue is then chromatographed onsilica, eluting with a toluene/acetone (80:20 to 70:30; v/v) mixture.252 mg of the expected product are obtained.

E) 5-(2,6-Dimethoxyphenyl)-1- 4- N-methyl-N- 3-N'-methyl-N'-(benzyloxycarbonyl)amino!propyl!carbamoyl!-2-isopropylphenyl!-3-pyrazolecarboxylicacid.

The compound obtained in the preceding step (252 mg) is dissolved in 2.5ml of dioxane and 90 μl of aqueous potassium hydroxide solution (1g/ml). After 24 hours of stirring, the medium is acidified with 1 ml ofconcentrated HCl. It is extracted with AcOEt, and the organic phase isthen dried over MgSO₄ to obtain 236 mg of the expected compound.

F) 5-(2,6-Dimethoxyphenyl)-1- 4- N-methyl-N- 3-N'-methyl-N'-(benzyloxycarbonyl)amino!propyl!carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid tert-butyl ester.

The acid obtained in the preceding step is dissolved in 2 ml ofacetonitrile, 0.5 ml of carbon tetrachloride and 158 mg oftriphenylphosphine are added and the mixture is left stirring for 2hours.

110 mg of the compound prepared in step C and 100 μl of triethylamineare added to the acid chloride thus formed. Triethylamine hydrochlorideprecipitates and the mixture is left stirring for 15 minutes. Water isadded and the mixture is then extracted with DCM; the organic phase isdried over MgSO₄ and concentrated under vacuum. The residue ischromatographed on silica, eluting with a toluene/acetone (80:20; v/v)mixture to obtain 323 mg of the expected product.

G) 5-(2,6-Dimethoxyphenyl)-1- 4- N-methyl-N- 3-N'-methylamino!propyl!carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid tert-butyl ester hydrochloride.

A mixture containing the compound of the preceding step (323 mg), 2 mgof Pd/C and 40 μl of concentrated HCl in 15 ml of ethanol is stirred for24 hours under a hydrogen atmosphere. The catalyst is filtered off andthe filtrate is evaporated under vacuum. The medium is taken up withether and stirred. The white precipitate formed is filtered off to give190 mg of the expected product.

NMR (CD₃ OD): 1.1:d:6H; 1.5:s:9H; 1.7-1.9:u.c.:8H; 2.2-2.3:u.c.:6H;2.6:s: 2.7-2.9:q+s:4H; 3:s:3H; 3.1:t:2H; 3.7: s+mt:8H; 6.6:d:2H;6.8:s:1H; 7.2-7.6:u.c.: 5H.

H) 2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylicacid hydrochloride.

The compound of the preceding step (190 mg) is suspended in 50 μl ofacetonitrile, and 0.5 ml of a solution of methyl iodide in toluene (89μl of methyl iodide in 100 ml of toluene) and 7.6 mg of silver carbonateare added. The insoluble matter is filtered off and the solvent is thenevaporated off under vacuum. The medium is taken up with 2 ml of formicacid and 0.2 ml of concentrated HCl and stirred overnight. Afterevaporation under vacuum and trituration in ether, 90 mg of the expectedproduct are obtained.

EXAMPLE 88

Oxazolone of the compound of EXAMPLE 1': ##STR122##

A solution 0.23 g of the compound of EXAMPLE 1' in 2 ml of DCM and 0.5ml anhydride is stirred for 4 hours 30 minutes. It is evaporated undervacuum, and the residue is triturated in pentane, filtered off and driedto obtain 230 ml expected oxazolone, m.p.=129 ' C. (dec.). IR (KBr):1800 cm¹. Mass spectrum:M:667.9.

NMR: 1:d:6H; 1.5-1.9:u.c.:8H ; 2:ba: 8H; 2.1-2.5:u.c.:6H; 2.65:qt:1H;2.9 and 3 :2s :3H; 3.1:mt:2H; 3.4:mt:2H; 3.65:s:6H; 6.6: :d:2H;6.9:s:1H; 7.1-7.4:u.c.:4H.

We claim:
 1. Compound of formula: ##STR123## in which: --R₁ represents agroup chosen from:--T--CN; --C(NH₂)═NOH; --C(═NOH)NH(CH₂)_(r) NR₅ R₆ ;--T--C(NR₁₂ R₁₃)═NR₁₄ ; --C(NH₂)═NO(CH₂)_(r) NR₅ R₆ ; --T--CONR_(a)R_(b) ; --T--CONR₇ R_(c) ; --Y--CO₂ R₇ ; --OR_(d) ; --T--NR₅ R₆, oncondition that R₅ and R₆ do not simultaneously represent hydrogen when Trepresents a direct bond; --T--N(R₇)COR_(e) ; --SO₂ NR_(a) R_(b) ;--T--N(R₇)SO₂ R'₇ ; --T--NR₂₇ R₂₈ ; --NR_(a) R_(b) represents a groupchosen from: --NR₅ R₆ ; --NR₉ (CH₂)_(s) CR₇ R₈ (CH₂)_(t) NR₅ R₆ ; --NR₂₁(CH₂)_(s) CR₇ R₈ (CH₂)_(t) R₂₂ R₂₃ R₂₄ Q.sup.⊖ --NR₇ (CH₂)_(q) CN; --NR₇(CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄ ; --NR₇ (CH₂)_(q) CONH₂ :--NR₇ (CH₂)_(q) CO₂R₇ ; --NR₂₁ (CH₂)_(s) CR₇ R₈ (CH₂)_(t) NR₂₅ R₂₆ ; --R_(c) represents agroup chosen from:--X--OR₇ ; --CHR₂₀ CO₂ R₇ ; --(CH₂)₄ CH(NH₂)CO₂ R₇ ;--R_(d) represents a group chosen from:--X--NR₅ R₆ ; --Y--CONR₅ R₆ ;--Y--CO₂ R₇ ; --Y--SO₂ NR₅ R₆ ; --R_(e) represents a group chosenfrom:--R₁₆ ; --Y--NR₅ R₆, --Y--NHCOR₁₆ ; --CH(R₁₇)NR₅ R₆ ; --Y--R₂₂ R₂₃R₂₄ Q.sup.⊖ ; --(CH₂)_(q) CN; --(CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄ ; --NR₁₈ R₁₉; --R₂ and R₃ each independently represent hydrogen, a (C₁ -C₆)alkyl, a(C₃ -C₈)cycloalkylmethyl, a (C₃ -C₈)cycloalkyl, a halogen, a nitro, atrifluoromethyl, a group --OR₄, a group --NR₅ R₆, a cyano, a carbamoyl;--or R₂ and R₃ together constitute a trimethylene, tetramethylene orpentamethylene group; --R₄ represents hydrogen; a (C₁ -C₆)alkyl; a (C₃C₄)alkenyl; a (C₃ C₈)cycloalkylene; a (C₃ C₈)cycloalkylmethyl; a (C₁-C₄)alkoxy(C₁ -C₄)alkylene; a benzyl; R₅ and R₆ each independentlyrepresent a hydrogen, a (C₁ -C₆)alkyl; a (C₃ -C₈)alkenyl; a (C₃-C₈)cycloalkylmethyl; --R'₅ and R'₆ each independently represent ahydrogen or a (C₁ -C₆)alkyl; --R'₇ represents a (C₁ -C₄)alkyl; a phenylwhich is unsubstituted or substituted one or more times with a (C₁-C₄)alkyl; a group --X--NR₅ R₆ ; --R₇ represents a hydrogen, a (C₁-C₄)alkyl or a benzyl; R₈ represents a hydrogen, a (C₁ -C₄)alkyl, ahydroxyl, or R₇ and R₈, together with the carbon atom to which they areattached, constitute a (C₃ -C₅)cycloalkane; --R₉ represents hydrogen, a(C₁ -C₄)alkyl, a benzyl, a group --X--OH or a group --X--NR'₅ R'₆, a (C₃-C₈)alkenyl; --R₁₂ and R₁₃ each independently represent a hydrogen or a(C₁ -C₄)alkyl; --R₁₄ represents hydrogen. R₁₄ may, in addition,represent a (C₁ -C₄)alkyl when R₁₂ represents hydrogen and R₁₃represents a (C₁ -C₄)alkyl; --R₁₆ represents hydrogen, a (C₁ -C₈)alkyl,a (C₃ -C₈)cycloalkyl, a phenyl --R₁₇ represents a (C₁ -C₆)alkyl, aphenyl, a benzyl, a hydroxy(C₁ -C₄)alkyl, an amino(C₁ -C₄)alkyl; --R₁₈and R₁₉ each independently represent a hydrogen, a (C₁ -C₄)alkyl; R₁₈may, in addition, represent a group --(CH₂)_(q) -NR₅ R₆ ; --R₂₀represents hydrogen, a (C₁ -C₄)alkyl, a benzyl, a hydroxyphenylmethyl, ahydroxy(C₁ -C₄)alkyl, a mercapto(C₁ -C₄)alkyl; a --(CH₂)₃ -NH--C(═NH)NH₂group, a --(CH₂)₄ NH₂ g --R₂₁ represents a (C₁ -C₄)alkyl, an allyl or abenzyl; --R₂₂ and R₂₃ each independently represent a (C₁ -C₆)alkyl;--R₂₄ represents a (C₁ -C₄)alkyl, a benzyl, an allyl, a hydroxy(C₁-C₄)alkyl, a (C₁ -C₄)alkoxy(C₁ -C₄)alkyl; Q.sup.⊖ represents an anion;--R₂₅ represents hydrogen or a (C₁ -C₆)alkyl; --R₂₆ represents a (C₁-C₄)alkylcarbonyl, a benzyloxycarbonyl; a (C₁ -C₄)alkylcarbonyl; --R₂₇represents a hydrogen; a (C₁ -C₄)alkyl, a (C₁ -C₄)alkylcarbonyl; a group--CO--(CH₂)_(r) -OH; a group SO₂ R'₇ ; --R₂₈ represents a group --X--NR₅R₆ ; --s=0 to 3; --t=0 to 3, on the condition that (s+t), in a samegroup, is greater than or equal to 1; --r=2to 5; --q=1 to 5; --Trepresents a direct bond or (C₁ -C₇)alkylene; --X represents a (C₂-C₇)alkylene; --Y represents a (C₁ -C₇)alkylene: --Z represents a (C₂-C₆)alkylene: --the group --NH--AA(OH) represents the residue of anamino acid: ##STR124## where X_(a) is hydrogen and X'_(a) is hydrogen, a(C₁ -C₅)alkyl or a non-aromatic C₃ -C₁₅ carbocyclic radical; oralternatively, X_(a) and X'_(a), together with the carbon atom to whichthey are attached, form a non-aromatic C₃ -C₁₅ carbocycle; its salts andits quaternary ammonium salts formed with acyclic or cyclic tertiaryamines and its solvates.
 2. Compound according to claim 1 of formula(Ip): ##STR125## in which: --R_(1p) represents a group chosenfrom:--T--CN; --C(NH₂)═NOH; --C(═NOH)NH(CH₂)_(r) NR₅ R₆ ; --T'C(NR₁₂R₁₃)═NR₁₄ ; --C(NH₂)═NO(CH₂)_(r) NR₅ R₆ ; --T--CONR_(a) R_(b) ;--T--CONR₇ R_(c) ;--Y--CO₂ R₇ ; --OR_(d) ; --T--NR₅ R₆, on conditionthat R₅ and R₆ do not simultaneously represent hydrogen when Trepresents a direct bond; --T--N(R₇)COR_(e) ; --SO₂ NR_(a) R_(b) ;--T--N(R₇)SO₂ R'₇ ; --NR_(a) R_(b) represents a group chosen from:--NR₅R₆ ; --NR₉ (CH₂)_(s) CR₇ R₈ (CH₂)_(t) NR₅ R₆ ; --NR₇ (CH₂)_(q) CN; --NR₇(CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄ ; --R_(c) represents a group chosenfrom:--X--OR₇ ; --CHR₂₀ CO₂ R₇ ; --(CH₂)₄ CH(NH₂)CO₂ R₇ ; --R_(d)represents a group chosen from:--X--NR₅ R₆ ; --Y--CONR₅ R₆ ; --Y--CO₂OR₇ ; --Y--SO₂ NR₅ R₆ ; --R_(e) represents a group chosen from:--R₁₆ ;--Y--NR₅ R₆ ; --Y--NHCOR₁₆ ; --CH(R₁₇)NR₅ R₆ ; --(CH₂)_(q) CN;--(CH₂)_(q) C(NR₁₂ R₁₃)═NR₁₄ ; --NR₁₈ R₁₉ ; R_(2p) and R_(3p) eachindependently represent hydrogen, a (C₁ -C₆)alkyl, a (C₃-C₈)cycloalkylmethyl, a (C₃ -C₈)cycloalkyl, a halogen, a nitro, atrifluoromethyl, a group --OR₄, a group --NR₅ R₆ :a cyano, a carbamoyl;or R_(2p) and R_(3p) together constitute a trimethylene, tetramethyleneor pentamethylene group; --R_(4p) represents hydrogen; a (C₁ -C₆)alkyl;a (C₃ C4)alkenyl; a (C₃ C₈)cycloalkyl; a (C₃ -C₈)cycloalkylmethyl; a (C₁-C₄)alkoxy(C₁ -C₄)alkyl; a benzyl; R₅ and R₆ each independentlyrepresent a hydrogen, a (C₁ -C₆)alkyl; --R'₇ represents a (C₁ -C₄)alkyl;--R₇ represents a hydrogen, a (C₁ -C₄)alkyl or a benzyl; --R₈ representsa hydrogen, n (C₁ -C₄)alkyl, a hydroxyl, or R₇ and R₈, together with thecarbon atom to which they are attached, constitute a (C₃-C₈)cycloalkane; --R₉ represents hydrogen, a methyl, a group --X--OH ora group --X--NR₅ R₆ ; --R₁₂ and R₁₃ each independently represent ahydrogen or a (C₁ -C₄)alkyl; --R₁₄ represents hydrogen, R₁₄ may, inaddition, represent a (C₁ -C₄)alkyl when R₁₂ represents hydrogen and R₁₃represents a (C₁ -C₄)alkyl; --R₁₆ represents hydrogen, a (C₁ -C₈)alkyl,a (C₃ -C₈)cycloalkyl, a phenyl; --R₁₇ represents a (C₁ -C₆)alkyl, aphenyl, a benzyl, a hydroxy(C₁ -C₄)alkyl, an amino(C₁ -C₄)alkyl; --R₁₈and R₁₉ each independently represent a hydrogen, a (C₁ -C₄)alkyl; R₁₈may, in addition, represent a group --(CH₂)_(q) -N'R₅ R₆ ; --R₂₀represents hydrogen, a (C₁ -C₄)alkyl, a benzyl, a hydroxyphenylmethyl, ahydroxy(C₁ -C₄)alkyl, a mercapto(C₁ -C₄)alkyl; a --CH₂)₃ -NH--C(═NH)NH₂group, a --CH₂)₄ NH₂ group; --s=0 to 3; --t=0 to 3, on the conditionthat (s+t) is greater than or equal to 1; --r=2 to 5; --q=1 5; --Trepresents a direct bond or (C₁ -C₇)alkylene; --X represents a (C₂-C₇)alkylene; --Y represents a (C₁ -C₇)alkylene; --the group--NH--AA_(p) (OH) represents the residue of an amino acid: ##STR126##where X_(a) is hydrogen and X'_(a) is hydrogen, a (C₁ -C₈)alkyl or anon-aromatic C₃ -C₁₅ carbocyclic radical; or alternatively X_(a) andX'_(a), together with the carbon atom to which they are attached, form anon-aromatic C₃ -C₁₅ carbocycle; and its salts.
 3. Compound according toclaim 1 of formula: ##STR127## in which: --R"4 represents hydrogen, amethyl or a cyclopropylmethyl;--AA" (OH) represents a2-carboxy-2-adamantyl, α-carboxycyclohexylmethyl or 9-carboxybicyclo3.3.1!nonan-9-yl group; among the substituents w₂, w₃, w₄ and w₅, atleast one is hydrogen and at least one other is other than hydrogen,such that: either(i)w₅ is hydrogen; w₃ is hydrogen or methyl; w₂ is (C₁-C₄)alkyl, (C₃ -C₆)cycloalkyl, (C₁ -C₄)alkoxy, chlorine ortrifluoromethyl, or w₂ and w₃ together form a 1,4-butylene group; w₄ ischosen either from the following groups: (i1)dialkylaminoalkylaminocarbonyl ##STR128## (i2)dialkylaminoalkyl(N-methyl)aminocarbonyl ##STR129## (i3)dialkylaminoalkyl(N-ethyl)aminocarbonyl ##STR130## (i4)cyanoalkyl(N-methyl)aminocarbonyl ##STR131## (i5)aminoalkylaminocarbonyl H₂ N--ALK'--NH--CO-- (i6)aminoalkyl(N-methyl)aminocarbonyl ##STR132## (i7)(N'-methyl)-(N'-alkoxycarbonyl)aminoalkyl(N-methyl)carbonyl ##STR133##(i8) amidinoalkylaminocarbonyl ##STR134## (i11)alkylaminoalkyl(N-methyl)aminocarbonyl ##STR135## (i13)bis(dialkylaminoalkyl)aminocarbonyl (ALK₂ N--ALK')₂ N--CO-- (i14)aminocarbonylalkyl(N-methyl)aminocarbonyl ##STR136## (i15)carboxyalkyl(N-methyl)aminocarbonyl ##STR137## (i16) a group ofstructure ##STR138## (i22) aminocarbonyl H₂ N--CO-- (i26)dialkylaminoalkyl(N-methyl)aminosulphonyl ##STR139## (i27)dialkylaminoalkyl(N-benzyl)aminosulphonyl ##STR140## (i29)allylaminocarbonyl CH₂ =CH--CH₂ -NH--CO-- (i30)dialkylaminoalkyl(N-acetyl)amino ##STR141## (i31) dialkylaminoalkylamino##STR142## (i32) dialkylaminoalkylcarboxamido ##STR143## oralternatively w₄ is chosen from the following groups: (i34)glycinamidoH₂ N--CH₂ -CO--NH-- (i35) tosylamido ##STR144## (i36)aminoalkylsulphonamido H₂ N--ALK'--SO₂ NH-- or H₂ N--CH₂ -SO₂ NH-- (i37)trialkylammonioalkyl(N-methyl)aminocarbonyl salt ##STR145## ALK being(C₁ -C₄)alkyl and ALK' being (C₂ -C₅)alkylene; or (ii)w₂ and w₅ arehydrogen w₃ is chlorine w₄ is cyano or aminocarbonyl or (iii)w₂ and w₅are hydrogen, w₃ is isopropyl and w₄ is dialkylaminoalkylaminocarbonyl##STR146## ALK and ALK' being as defined above; or (iv) w₂ and w₅ arehydrogen, w₃ is dialkylaminoalkyl(N-methyl)aminocarbonyl ##STR147## andw₄ is chloro; ALK and ALK' being as defined above; or (v) w₃ and w₄ arehydrogen w₂ is chloro, (C₁ -C₄)alkoxy or (C₁ -C₄)alkyl w₅ is(v1)dialkylaminoalkyl(N-methyl)aminocarbonyl ##STR148## (v2)dialkylaminoalkylcarbonylamino ##STR149## ALK and ALK' being as definedabove; its internal salts and its pharmaceutically acceptable salts, itsquaternary ammonium salts and its solvates.
 4. Compound according toclaim 1 of formula: ##STR150## in which: R₁, R₂ and R₃ are as definedfor (I) in claim 1;R_(4y) represents hydrogen, a (C₁ -C₄)alkyl group, anallyl or a cyclopropylmethyl; and the group --NH--AA_(y) -(OH)represents the residue of 2-aminoadamantane-2-carboxylic acid or of(S)-α-aminocyclohexaneacetic acid or of 9-aminobicyclo-3.3.1!-nonane-9-carboxylic acid; its salts and its quaternary ammoniumsalts formed with acyclic or cyclic tertiary amines and its solvates. 5.Compound according to either of claims 1 or 4 of formula (Iy) inwhich:R₁, as defined for (I) in claim 1, is at position 4 or 5; R₂, isat position 2 and represents a group chosen from:hydrogen, a (C₁-C₆)alkyl, a (C₃ -C₈)cycloalkyl, a (C₃ -C₈)cycloalkylmethyl, a (C₁-C₆)alkoxy, a (C₃ -C₈)cycloalkyloxy, a chlorine, a trifluoromethyl; R₃is at position 3 and represents hydrogen, a (C₁ -C₆)alkyl, a (C₃-C₈)cycloalkyl, a (C₃ -C₈)cycloalkylmethyl; or R₂ and R₃ togetherconstitute a trimethylene, a tetramethylene or a pentamethylene; itssalts and its quaternary ammonium salts formed with acyclic or cyclictertiary amines and its solvates.
 6. Compound according to either ofclaims 1 and 4 of formula: ##STR151## in which: R_(4y) and NH--AA_(y)(OH) are as defined for (Iy) in claim 4; _(1x) is at position 4 or 5 andrepresents a group chosen from --T--CONR_(a) R_(b), --SO₂ NR_(a) R_(b),--T--NR₅ R₆, --N(R₇)COR_(e), OR_(d), --N(R₇)SO₂ R'₇, --T--NR₂₇ R₂₈ ; thegroups --T--, R_(a), R_(b), R_(d), R_(e), R₅, R₆, R₇, R'₇, R₂₇ and R₂₈being as defined for (I) in claim 1; R_(2x) and R_(3x) eachindependently represent hydrogen; a (C₁ -C₆)alkyl; a (C₃ -C₈)cycloalkyl;a (C₃ -C₈)cycloalkylmethyl; on condition that R_(2x) and R_(3x) do notsimultaneously represent hydrogen; or R_(2x) and R_(3x) togetherconstitute a tetramethylene group; its salts and its quaternary ammoniumsalts formed with acyclic or cyclic tertiary amines and its solvates. 7.Compound according to claim 1 of formula: ##STR152## in which R₄ y,R_(1x) and NH--AA_(y) (OH) are as defined in claims 4 and 6; its saltsand its quaternary ammonium salts formed with acyclic or cyclic tertiaryamines.
 8. Compound of formula: ##STR153## in which: R_(1x), R_(2x) andR_(3x) are as defined for (Ix) in claim 6; its salts and its quaternaryammonium salts formed with acyclic or cyclic tertiary amines and itssolvates.
 9. 2- 5-(2,6-Dimethoxyphenyl)-1- 4-N-methyl-N-(3-dimethylaminopropyl)carbamoyl!-2-isopropylphenyl!-3-pyrazolylcarbonylamino!-2-adamantanecarboxylic acid, its internal salts and its saltswhich are preferably pharmaceutically acceptable, and its solvates. 10.A compound of formula: ##STR154## in which R₁, R₂, R₃ and R₄ have thedefinitions given for the compounds (I) in claim 1, and R'₁ represents aprecursor of R₁ chosen from nitro, amino, phthalimido, hydroxyl,hydroxy(C₁ -C₇)alkylene, sulpho, cyano, (C₁ -C₄)alkoxycarbonyl andbenzyloxycarbonyl groups, on condition R'₁ is not a nitro, amino orhydroxyl group when R₂ or R₃ represents hydrogen, a (C₁ -C₄):alkyl, a(C₁ -C₄)alkoxy, a trifluoromethyl, a nitro, a halogeno or an aminogroup;and its acid derivatives.
 11. Compound according to claim 2 inwhich the acid derivative is an acid chloride, a C₁ -C₄ alkyl ester ormixed anhydride with isobutyl chloroformate or ethyl chloroformate. 12.A pharmaceutical composition containing an effective amount of acompound according to claim 1 or of one of its pharmaceuticallyacceptable salts, in combination with a pharmaceutically acceptablevehicle.